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Han C, Liu S, Ye S, Chen K, Chen D, Wang K, Liang W, Zhong S, Liu L, Li S, Chen W, Li Q. Genome-wide identification, evolution and expression of pax gene family members in mandarin fish (Siniperca chuatsi). COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2025; 54:101423. [PMID: 39842301 DOI: 10.1016/j.cbd.2025.101423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/31/2024] [Accepted: 01/16/2025] [Indexed: 01/24/2025]
Abstract
The pax gene family is involved in the development process through its extensive effects on cell proliferation, differentiation, and apoptosis. Herein, the whole pax gene family members of mandarin fish (Siniperca chuatsi) were first identified and characterized. By comparing pax gene family members from another 13 representative animals, an expansion of pax gene family members was observed in teleosts. In mandarin fish, a total of 15 potential pax gene family members, distributed on 13 chromosomes, were found, which shared conserved synteny with other teleosts. The expression profiles revealed that members of pax gene family showed time-specific expression profiles during embryonic and gonad development in mandarin fish, which indicated they might play a specific role in organogenesis during embryonic development and the process of gonad development and differentiation. Our research will lay a good foundation for further functional investigation of pax gene family during fish embryonic and gonad development.
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Affiliation(s)
- Chong Han
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China.
| | - Shiyan Liu
- State Key Laboratory of Biocontrol and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou 510275, China
| | - Shuzheng Ye
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China
| | - Kaichun Chen
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China
| | - Dingxian Chen
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China
| | - Kaifeng Wang
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China
| | - Weiqian Liang
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China
| | - Simin Zhong
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China
| | - Lanyuan Liu
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China
| | - Sipeng Li
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China
| | - Weijian Chen
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China
| | - Qiang Li
- Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China.
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Jin Y, Xie X, Li H, Zhang M. The role of homeobox gene Six1 in cancer progression and its potential as a therapeutic target: A review. Int J Biol Macromol 2025; 308:142666. [PMID: 40164243 DOI: 10.1016/j.ijbiomac.2025.142666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 03/19/2025] [Accepted: 03/28/2025] [Indexed: 04/02/2025]
Abstract
The sine oculis homeobox gene 1 (Six1), a member of the Six transcription factor family, specifically binds to defined DNA regions, regulates target gene expression, and plays a crucial role in various tissue and organ development processes. Moreover, Six1 is a critical factor in cancer progression and prognosis making it a central focus in cancer research. Consequently, a comprehensive review of involvement of the Six1 gene in cancer research has a high relevance. This review synthesizes findings from other researches, examines the gene structure and protein functionality of Six1, summarizes its relationship with various cancers, elucidates its mechanisms in promoting tumor progression and development, explores potential possibilities for targeting Six1 as a therapeutic approach for cancer treatment. Six1 is correlated with tumor malignancy and poor prognosis, plays a critical role in promoting tumor cell proliferation, invasion, metastasis, and energy metabolism. Targeting Six1 degradation or expression can potentially suppress tumor progression. This review aims to enhance our understanding of the function and significance of Six1 in cancers while providing a valuable reference for Six1-based cancer diagnosis, prognosis, and therapeutic interventions. This knowledge will facilitate more in-depth oncology research related to Six1, particularly in identifying drug resistance mechanisms and developing precision-targeted therapies.
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Affiliation(s)
- Yong Jin
- Department of Rheumatology and Immunology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China; Inner Mongolia Key Laboratory for Pathogenesis and Diagnosis of Rheumatic and Autoimmune Diseases, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Xinran Xie
- School of Basic Medicine sciences, Inner Mongolia Medical University, Hohhot, China
| | - Hongbin Li
- Department of Rheumatology and Immunology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China; Inner Mongolia Key Laboratory for Pathogenesis and Diagnosis of Rheumatic and Autoimmune Diseases, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
| | - Manling Zhang
- Department of Rheumatology and Immunology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China; Inner Mongolia Key Laboratory for Pathogenesis and Diagnosis of Rheumatic and Autoimmune Diseases, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
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Huang Z, Hu L, Liu Z, Wang S. The Functions and Regulatory Mechanisms of Histone Modifications in Skeletal Muscle Development and Disease. Int J Mol Sci 2025; 26:3644. [PMID: 40332229 PMCID: PMC12027200 DOI: 10.3390/ijms26083644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/05/2025] [Accepted: 04/09/2025] [Indexed: 05/08/2025] Open
Abstract
Skeletal muscle development is a complex biological process regulated by many factors, such as transcription factors, signaling pathways, and epigenetic modifications. Histone modifications are important epigenetic regulatory factors involved in various biological processes, including skeletal muscle development, and play a crucial role in the pathogenesis of skeletal muscle diseases. Histone modification regulators affect the expression of many genes involved in skeletal muscle development and disease by adding or removing certain chemical modifications. In this review, we comprehensively summarize the functions and regulatory activities of the histone modification regulators involved in skeletal muscle development, regeneration, and disease.
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Affiliation(s)
- Zining Huang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan 430062, China; (Z.H.); (L.H.)
| | - Linqing Hu
- State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan 430062, China; (Z.H.); (L.H.)
| | - Zhiwei Liu
- Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
| | - Shanshan Wang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan 430062, China; (Z.H.); (L.H.)
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Ranganathan R, Sari F, Wang SX, Thiery A, Buzzi AL, Guerra R, Moody SA, Streit A. Targets of the transcription factor Six1 identify previously unreported candidate deafness genes. Development 2025; 152:dev204533. [PMID: 40213817 PMCID: PMC12045605 DOI: 10.1242/dev.204533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/12/2025] [Indexed: 05/03/2025]
Abstract
Branchio-otic (BOS) and branchio-oto-renal (BOR) syndromes are autosomal dominant disorders featuring multiple birth defects including ear, renal and branchial malformations. Mutations in the homeodomain transcription factor SIX1 and its co-factor EYA1 have been identified in about 50% of individuals with BOS or BOR, while causative mutations are unknown in the other half. We hypothesise that SIX1 target genes represent new BOS and BOR candidates. Using published transcriptomic and epigenomic data from chick ear progenitors, we first identify putative Six1 targets. Next, we provide evidence that Six1 directly regulates some of these candidates: Six1 binds to their enhancers, and functional experiments in Xenopus and chick confirm that Six1 controls their expression. Finally, we show that most putative chick Six1 targets are also expressed in the human developing ear and are associated with known deafness loci. Together, our results not only characterise the molecular mechanisms that mediate Six1 function in the developing ear, but also provide new candidates for human congenital deafness.
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Affiliation(s)
- Ramya Ranganathan
- Centre for Craniofacial and Regenerative Biology, King's College London, London SE1 9RT, UK
| | - Fereshteh Sari
- Centre for Craniofacial and Regenerative Biology, King's College London, London SE1 9RT, UK
| | - Scarlet Xiaoyan Wang
- Centre for Craniofacial and Regenerative Biology, King's College London, London SE1 9RT, UK
| | - Alexandre Thiery
- Centre for Craniofacial and Regenerative Biology, King's College London, London SE1 9RT, UK
| | - Ailin Leticia Buzzi
- Centre for Craniofacial and Regenerative Biology, King's College London, London SE1 9RT, UK
| | - Rosalinda Guerra
- Centre for Craniofacial and Regenerative Biology, King's College London, London SE1 9RT, UK
| | - Sally A. Moody
- Department of Anatomy & Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA
| | - Andrea Streit
- Centre for Craniofacial and Regenerative Biology, King's College London, London SE1 9RT, UK
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Shi S, Li X, Alderman C, Huang W, Wick L, Foulon N, Rossi J, Hu W, Cui S, Zheng H, Taylor DJ, Ford HL, Zhao R. Cryo-EM structures reveal the PP2A-B55α and Eya3 interaction that can be disrupted by a peptide inhibitor. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.04.636346. [PMID: 39975004 PMCID: PMC11838537 DOI: 10.1101/2025.02.04.636346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
We have previously shown that Eya3 recruits PP2A-B55α to dephosphorylate pT58 on Myc, increasing Myc stability and enhancing primary tumor growth of triple-negative breast cancer (TNBC). However, the molecular details of how Eya3 recruits PP2A-B55α remain unclear. Here we determined the cryo-EM structures of PP2A-B55α bound with Eya3, with an inhibitory peptide B55i, and in its unbound state. These studies demonstrate that Eya3 binds B55α through an extended peptide in the NTD of Eya3. The Eya3 peptide and other PP2A-B55α substrates and protein/peptide inhibitors including B55i bind to a similar area on the B55α surface but the molecular details of the binding differ. We further demonstrated that the B55i peptide inhibits the B55α and Eya3 interaction in vitro. B55i peptide expressed on a plasmid increases pT58 and decreases Myc protein level in TNBC cells, suggesting the potential of B55i or similar peptides as therapies for TNBC.
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Lan YZ, Wu Z, Chen WJ, Yu XN, Wu HT, Liu J. Sine oculis homeobox homolog family function in gastrointestinal cancer: Progression and comprehensive analysis. World J Clin Oncol 2025; 16:97163. [PMID: 39867730 PMCID: PMC11528897 DOI: 10.5306/wjco.v16.i1.97163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 09/20/2024] [Accepted: 10/20/2024] [Indexed: 10/30/2024] Open
Abstract
The sine oculis homeobox homolog (SIX) family, a group of transcription factors characterized by a conserved DNA-binding homology domain, plays a critical role in orchestrating embryonic development and organogenesis across various organisms, including humans. Comprising six distinct members, from SIX1 to SIX6, each member contributes uniquely to the development and differentiation of diverse tissues and organs, underscoring the versatility of the SIX family. Dysregulation or mutations in SIX genes have been implicated in a spectrum of developmental disorders, as well as in tumor initiation and progression, highlighting their pivotal role in maintaining normal developmental trajectories and cellular functions. Efforts to target the transcriptional complex of the SIX gene family have emerged as a promising strategy to inhibit tumor development. While the development of inhibitors targeting this gene family is still in its early stages, the significant potential of such interventions holds promise for future therapeutic advances. Therefore, this review aimed to comprehensively explore the advancements in understanding the SIX family within gastrointestinal cancers, focusing on its critical role in normal organ development and its implications in gastrointestinal cancers, including gastric, pancreatic, colorectal cancer, and hepatocellular carcinomas. In conclusion, this review deepened the understanding of the functional roles of the SIX family and explored the potential of utilizing this gene family for the diagnosis, prognosis, and treatment of gastrointestinal cancers.
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Affiliation(s)
- Yang-Zheng Lan
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xin-Ning Yu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Gustafson AL, Durbin AD, Artinger KB, Ford HL. Myogenesis gone awry: the role of developmental pathways in rhabdomyosarcoma. Front Cell Dev Biol 2025; 12:1521523. [PMID: 39902277 PMCID: PMC11788348 DOI: 10.3389/fcell.2024.1521523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 12/23/2024] [Indexed: 02/05/2025] Open
Abstract
Rhabdomyosarcoma is a soft-tissue sarcoma that occurs most frequently in pediatric patients and has poor survival rates in patients with recurrent or metastatic disease. There are two major sub-types of RMS: fusion-positive (FP-RMS) and fusion-negative (FN-RMS); with FP-RMS typically containing chromosomal translocations between the PAX3/7-FOXO1 loci. Regardless of subtype, RMS resembles embryonic skeletal muscle as it expresses the myogenic regulatory factors (MRFs), MYOD1 and MYOG. During normal myogenesis, these developmental transcription factors (TFs) orchestrate the formation of terminally differentiated, striated, and multinucleated skeletal muscle. However, in RMS these TFs become dysregulated such that they enable the sustained properties of malignancy. In FP-RMS, the PAX3/7-FOXO1 chromosomal translocation results in restructured chromatin, altering the binding of many MRFs and driving an oncogenic state. In FN-RMS, re-expression of MRFs, as well as other myogenic TFs, blocks terminal differentiation and holds cells in a proliferative, stem-cell-like state. In this review, we delve into the myogenic transcriptional networks that are dysregulated in and contribute to RMS progression. Advances in understanding the mechanisms through which myogenesis becomes stalled in RMS will lead to new tumor-specific therapies that target these aberrantly expressed developmental transcriptional pathways.
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Affiliation(s)
- Annika L. Gustafson
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Molecular Biology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Adam D. Durbin
- Division of Molecular Oncology, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - Kristin B. Artinger
- Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, MN, United States
| | - Heide L. Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Molecular Biology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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Han M, Wang X, Du H, Cao Y, Zhao Z, Niu S, Bao X, Rong Y, Ao X, Guo F, Xia Q, Shang F, Wang R, Zhang Y. Genome-wide association study identifies candidate genes affecting body conformation traits of Zhongwei goat. BMC Genomics 2025; 26:37. [PMID: 39810085 PMCID: PMC11730152 DOI: 10.1186/s12864-024-11097-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 11/27/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Identifying markers or genes crucial for growth traits in Zhongwei goats is pivotal for breeding. Pinpointing genetic factors linked to body size gain enhances breeding efficiency and economic value. In this study, we used the MGISEQ-T7 platform to re-sequence 240 Zhongwei goats (133 male; 107 female) belonging to 5 metrics of growth traits at different growth stages (40 days and 6 months, here in after referred to as 40d and 6 m), namely, Body Weight (BW), Body Height (BH), Body Length (BL), Chest Circumference (CC), Tube Circumference (TC) were examined. A Genome-wide association study (GWAS) was conducted to identify candidate genes associated with the five indicators of body conformation traits, thereby establishing a foundation for subsequent investigations into the biological functions of these genes. RESULTS A total of 19.89 Tb of raw data was generated with an average sequencing depth of about 20×. After quality control, 15,958,716 SNPs were available for the analysis. A total of 342 genome-wide significant SNPs were obtained. Among them, in the two physiological stages of 40d and 6 m, 147 and 32 SNPs were significantly associated with BW; 1 and 4 SNPs were significantly associated with BH; 19 and 6 SNPs were significantly associated with BL; 33 and 64 SNPs were significantly associated with CC, 34 and 2 SNPs were significantly associated with TC. These SNPs were annotated to 425 candidate genes. Finally, A total of 39 candidate genes are closely related to biological processes such as skeletal muscle development, skeletal formation, carcass quality, and embryonic development, where ADIPOQ, CCDD39, PTPRT, ZNF215, VRTN, ABCD4, DLST, ADAMTS2, ROBO1, AKAP13, AQPI, SOX2, and AHSG were identified as an important component of the genetic framework that may control somatic conformational traits in Zhongwei goats. which warrants further investigation and review. We verified the polymorphism of 11 SNPs by KASP, and found that Chr13_g.11,700,438 A > G, Chr15_g.37,120,328 A > G, Chr6_g.7,209,383 C > T, Chr20_g.51277932T > A, Chr19_g.17,078,199 A > G, and Chr1_g.79,943,276 C > T were significantly genotyped in verified populations (P < 0.001). CONCLUTION It is the first GWAS study to analyze genomic data from 40d and 6 m of Zhongwei goats to understand the molecular genetic mechanisms of growth. Our research identified a series of SNPs and candidate genes associated with growth traits, which could assist us in developing the meat production trait in Zhongwei goats.
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Affiliation(s)
- Mingxuan Han
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Xinbo Wang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Haidong Du
- Zhongwei Goat Breeding Farm, Zhongwei, 755006, China
| | - Yanlong Cao
- Zhongwei Goat Breeding Farm, Zhongwei, 755006, China
| | | | - Shuran Niu
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Xuxu Bao
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Youjun Rong
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Xiaofang Ao
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Furong Guo
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Qincheng Xia
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Fangzheng Shang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Ruijun Wang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China.
- Key Laboratory of Mutton Sheep Genetics and Breeding, Ministry of Agriculture, Hohhot, 010018, China.
- Key Laboratory of Goat and Sheep Genetics, Breeding and Reproduction in Inner Mongolia Autonomous Region, Hohhot, 010018, China.
| | - Yanjun Zhang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China.
- Key Laboratory of Mutton Sheep Genetics and Breeding, Ministry of Agriculture, Hohhot, 010018, China.
- Key Laboratory of Goat and Sheep Genetics, Breeding and Reproduction in Inner Mongolia Autonomous Region, Hohhot, 010018, China.
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Xu L, Wang X, Wu J, Wang H, Zhou W, Liu J, Ni M, Zhang K, Yu B, Lin R. Genetic variation analysis of Guanling cattle based on whole-genome resequencing. Anim Biosci 2024; 37:2044-2053. [PMID: 38938024 PMCID: PMC11541021 DOI: 10.5713/ab.24.0181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/12/2024] [Accepted: 06/18/2024] [Indexed: 06/29/2024] Open
Abstract
OBJECTIVE The objective of this study was to unravel the genetic traits of Guanling cattle, pinpoint genes advantageous for muscle growth, and lay a foundation for the preservation of genetic diversity and further analysis of regulation mechanism of important economic traits in local cattle breed. METHODS In this study, we sequenced the whole genome of 3 Guanling cattle in Guizhou province using the Illumina HiSeq cBo sequencing platform. And, high- multiplex polymerase chain reaction technology was employed to detect high-quality single nucleotide polymorphism (SNP) sites of other 55 Guanling cattle. RESULTS Our study identified 166,411 non-synonymous SNPs (nsSNPs) and 42,423 insertions and deletions (indels). Through SNP annotation, gene function enrichment analysis, and comparing with Simmental, Angus, and Limousin cattle, we identified six genes (LEPR, AKAP9, SIX4, SPIDR, PRG4, FASN) which are potentially influential on meat quality traits, playing crucial roles in muscle growth, fat metabolism, and bodily support. We also examined polymorphisms at seven SNP sites in Guanling cattle and found that all seven were in Hardy-Weinberg equilibrium. CONCLUSION These findings suggested that these gene sites are stable and widespread in the Guanling cattle population. Our research lays the groundwork for future genetic enhancement and variety identification of Guanling cattle.
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Affiliation(s)
- Longxin Xu
- Institute of Animal Husbandry and Veterinary Science, Guizhou Academy of Agricultural Sciences, Guiyang 550005,
China
| | - Xin Wang
- Institute of Animal Husbandry and Veterinary Science, Guizhou Academy of Agricultural Sciences, Guiyang 550005,
China
| | - Junda Wu
- Institute of Animal Husbandry and Veterinary Science, Guizhou Academy of Agricultural Sciences, Guiyang 550005,
China
| | - Hua Wang
- Institute of Animal Husbandry and Veterinary Science, Guizhou Academy of Agricultural Sciences, Guiyang 550005,
China
| | - Wenzhang Zhou
- Institute of Animal Husbandry and Veterinary Science, Guizhou Academy of Agricultural Sciences, Guiyang 550005,
China
| | - Jing Liu
- Institute of Animal Husbandry and Veterinary Science, Guizhou Academy of Agricultural Sciences, Guiyang 550005,
China
| | - Mengmeng Ni
- College of Animal Sciences, Guizhou University, Guiyang 550000,
China
- Guizhou Yellow Cattle Industry Group Co., Ltd, Guiyang 550001,
China
| | - Kaikai Zhang
- Institute of Animal Husbandry and Veterinary Science, Guizhou Academy of Agricultural Sciences, Guiyang 550005,
China
| | - Bo Yu
- Institute of Animal Husbandry and Veterinary Science, Guizhou Academy of Agricultural Sciences, Guiyang 550005,
China
| | - Ruiyi Lin
- College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002,
China
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10
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Rich J, Bennaroch M, Notel L, Patalakh P, Alberola J, Issa F, Opolon P, Bawa O, Rondof W, Marchais A, Dessen P, Meurice G, Le-Gall M, Polrot M, Ser-Le Roux K, Mamchaoui K, Droin N, Raslova H, Maire P, Geoerger B, Pirozhkova I. DiPRO1 distinctly reprograms muscle and mesenchymal cancer cells. EMBO Mol Med 2024; 16:1840-1885. [PMID: 39009887 PMCID: PMC11319797 DOI: 10.1038/s44321-024-00097-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 07/17/2024] Open
Abstract
We have recently identified the uncharacterized ZNF555 protein as a component of a productive complex involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. Subsequently named DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1), our study provides substantial evidence of its role in the differentiation and proliferation of human myoblasts. DiPRO1 operates through the regulatory binding regions of SIX1, a master regulator of myogenesis. Its relevance extends to mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma, where DiPRO1 acts as a repressor via the epigenetic regulators TIF1B and UHRF1, maintaining methylation of cis-regulatory elements and gene promoters. Loss of DiPRO1 mimics the host defense response to virus, awakening retrotransposable repeats and the ZNF/KZFP gene family. This enables the eradication of cancer cells, reprogramming the cellular decision balance towards inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, our results highlight the vulnerability of mesenchymal cancer tumors to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential therapeutic target.
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Affiliation(s)
- Jeremy Rich
- UMR8126 CNRS, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Melanie Bennaroch
- UMR8126 CNRS, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Laura Notel
- UMR8126 CNRS, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Polina Patalakh
- UMR8126 CNRS, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Julien Alberola
- UMR8126 CNRS, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Fayez Issa
- INSERM U1016, CNRS UMR 8104, Institut Cochin, Université Paris-Cité, Paris, France
| | - Paule Opolon
- Pathology and Cytology Section, UMS AMMICA, CNRS, INSERM, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Olivia Bawa
- Pathology and Cytology Section, UMS AMMICA, CNRS, INSERM, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Windy Rondof
- Bioinformatics Platform, UMS AMMICA, CNRS, INSERM, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer campus, INSERM U1015, Université Paris-Saclay, Villejuif, France
| | - Antonin Marchais
- Bioinformatics Platform, UMS AMMICA, CNRS, INSERM, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer campus, INSERM U1015, Université Paris-Saclay, Villejuif, France
| | - Philippe Dessen
- Bioinformatics Platform, UMS AMMICA, CNRS, INSERM, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Guillaume Meurice
- Bioinformatics Platform, UMS AMMICA, CNRS, INSERM, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Morgane Le-Gall
- Proteom'IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, F-75014, Paris, France
| | - Melanie Polrot
- Pre-clinical Evaluation Unit (PFEP), INSERM, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Karine Ser-Le Roux
- Pre-clinical Evaluation Unit (PFEP), INSERM, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Kamel Mamchaoui
- Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, F-75013, Paris, France
| | - Nathalie Droin
- Genomic Platform, UMS AMMICA US 23 INSERM UAR 3655 CNRS, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
- UMR1287 INSERM, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Hana Raslova
- UMR1287 INSERM, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France
| | - Pascal Maire
- INSERM U1016, CNRS UMR 8104, Institut Cochin, Université Paris-Cité, Paris, France
| | - Birgit Geoerger
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer campus, INSERM U1015, Université Paris-Saclay, Villejuif, France
| | - Iryna Pirozhkova
- UMR8126 CNRS, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France.
- INSERM U1016, CNRS UMR 8104, Institut Cochin, Université Paris-Cité, Paris, France.
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11
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Wang Q, Han R, Xing H, Li H. A consensus genome of sika deer (Cervus nippon) and transcriptome analysis provided novel insights on the regulation mechanism of transcript factor in antler development. BMC Genomics 2024; 25:617. [PMID: 38890595 PMCID: PMC11186158 DOI: 10.1186/s12864-024-10522-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 06/13/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Sika deer (Cervus nippon) holds significance among cervids, with three genomes recently published. However, these genomes still contain hundreds of gaps and display significant discrepancies in continuity and accuracy. This poses challenges to functional genomics research and the selection of an appropriate reference genome. Thus, obtaining a high-quality reference genome is imperative to delve into functional genomics effectively. FINDINGS Here we report a high-quality consensus genome of male sika deer. All 34 chromosomes are assembled into single-contig pseudomolecules without any gaps, which is the most complete assembly. The genome size is 2.7G with 23,284 protein-coding genes. Comparative genomics analysis found that the genomes of sika deer and red deer are highly conserved, an approximately 2.4G collinear regions with up to 99% sequence similarity. Meanwhile, we observed the fusion of red deer's Chr23 and Chr4 during evolution, forming sika deer's Chr1. Additionally, we identified 607 transcription factors (TFs) that are involved in the regulation of antler development, including RUNX2, SOX6, SOX8, SOX9, PAX8, SIX2, SIX4, SIX6, SPI1, NFAC1, KLHL8, ZN710, JDP2, and TWST2, based on this consensus reference genome. CONCLUSIONS Our results indicated that we acquired a high-quality consensus reference genome. That provided valuable resources for understanding functional genomics. In addition, discovered the genetic basis of sika-red hybrid fertility and identified 607 significant TFs that impact antler development.
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Affiliation(s)
- Qianghui Wang
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, China
| | - Ruobing Han
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, China
| | - Haihua Xing
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, China
| | - Heping Li
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, China.
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12
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Kahane N, Dahan-Barda Y, Kalcheim C. A Spatio-Temporal-Dependent Requirement of Sonic Hedgehog in the Early Development of Sclerotome-Derived Vertebrae and Ribs. Int J Mol Sci 2024; 25:5602. [PMID: 38891790 PMCID: PMC11171667 DOI: 10.3390/ijms25115602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/13/2024] [Accepted: 05/19/2024] [Indexed: 06/21/2024] Open
Abstract
Derived from axial structures, Sonic Hedgehog (Shh) is secreted into the paraxial mesoderm, where it plays crucial roles in sclerotome induction and myotome differentiation. Through conditional loss-of-function in quail embryos, we investigate the timing and impact of Shh activity during early formation of sclerotome-derived vertebrae and ribs, and of lateral mesoderm-derived sternum. To this end, Hedgehog interacting protein (Hhip) was electroporated at various times between days 2 and 5. While the vertebral body and rib primordium showed consistent size reduction, rib expansion into the somatopleura remained unaffected, and the sternal bud developed normally. Additionally, we compared these effects with those of locally inhibiting BMP activity. Transfection of Noggin in the lateral mesoderm hindered sternal bud formation. Unlike Hhip, BMP inhibition via Noggin or Smad6 induced myogenic differentiation of the lateral dermomyotome lip, while impeding the growth of the myotome/rib complex into the somatic mesoderm, thus affirming the role of the lateral dermomyotome epithelium in rib guidance. Overall, these findings underscore the continuous requirement for opposing gradients of Shh and BMP activity in the morphogenesis of proximal and distal flank skeletal structures, respectively. Future research should address the implications of these early interactions to the later morphogenesis and function of the musculo-skeletal system and of possible associated malformations.
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Affiliation(s)
| | | | - Chaya Kalcheim
- Department of Medical Neurobiology, Institute of Medical Research Israel-Canada (IMRIC) and the Edmond and Lily Safra Center for Brain Sciences (ELSC), Hebrew University of Jerusalem-Hadassah Medical School, P.O. Box 12272, Jerusalem 9112102, Israel; (N.K.); (Y.D.-B.)
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13
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Chen X, Ma J, Zhang T. Genetics and Epigenetics in the Genesis and Development of Microtia. J Craniofac Surg 2024; 35:00001665-990000000-01343. [PMID: 38345940 PMCID: PMC11045557 DOI: 10.1097/scs.0000000000010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 12/03/2023] [Indexed: 04/28/2024] Open
Abstract
Microtia is a congenital malformation of the external and middle ear associated with varying degrees of severity that range from mild structural abnormalities to the absence of the external ear and auditory canal. Globally, it is the second most common congenital craniofacial malformation and is typically caused by inherited defects, external factors, or the interaction between genes and external factors. Epigenetics notably represents a bridge between genetics and the environment. This review has devoted attention to the current proceedings of the genetics and epigenetics of microtia and related syndromes.
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Affiliation(s)
- Xin Chen
- Department of Facial Plastic and Reconstructive Surgery, ENT Institute, Eye & ENT Hospital, Fudan University
| | - Jing Ma
- Department of Facial Plastic and Reconstructive Surgery, ENT Institute, Eye & ENT Hospital, Fudan University
| | - Tianyu Zhang
- Department of Facial Plastic and Reconstructive Surgery, ENT Institute, Eye & ENT Hospital, Fudan University
- NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China
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14
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Alderman C, Krueger A, Rossi J, Ford HL, Zhao R. In Vitro Phosphatase Assays for the Eya2 Tyrosine Phosphatase. Methods Mol Biol 2024; 2743:285-300. [PMID: 38147222 DOI: 10.1007/978-1-0716-3569-8_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2023]
Abstract
Protein tyrosine phosphatases (PTP), such as the Eyes Absent (Eya) family of proteins, play important roles in diverse biological processes. In vitro phosphatase assays are essential tools for characterizing the enzymatic activity as well as discovering inhibitors and regulators of these phosphatases. Two common types of in vitro phosphatase assays use either a small molecule substrate that produces a fluorescent or colored product, or a peptide substrate that produces a colorimetric product in a malachite green assay. In this chapter, we describe detailed protocols of a phosphatase assay using small molecule 3-O-methylfluorescein phosphate (OMFP) as a substrate and a malachite green assay using the pH2AX peptide as a substrate to evaluate the phosphatase activity of EYA2 and the effect of small molecule inhibitors of EYA2. These protocols can be easily adapted to study other protein tyrosine phosphatases.
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Affiliation(s)
- Christopher Alderman
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Aaron Krueger
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- KBI Biopharma, Inc., Boulder, CO, USA
| | - John Rossi
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Heide L Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rui Zhao
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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15
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Grobbelaar S, Mercier AE, van den Bout I, Durandt C, Pepper MS. Considerations for enhanced mesenchymal stromal/stem cell myogenic commitment in vitro. Clin Transl Sci 2024; 17:e13703. [PMID: 38098144 PMCID: PMC10787211 DOI: 10.1111/cts.13703] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 11/16/2023] [Accepted: 12/09/2023] [Indexed: 01/15/2024] Open
Abstract
The generation of tissue from stem cells is an alluring concept as it holds a number of potential applications in clinical therapeutics and regenerative medicine. Mesenchymal stromal/stem cells (MSCs) can be isolated from a number of different somatic sources, and have the capacity to differentiate into adipogenic, osteogenic, chondrogenic, and myogenic lineages. Although the first three have been extensively investigated, there remains a paucity of literature on the latter. This review looks at the various strategies available in vitro to enhance harvested MSC commitment and differentiation into the myogenic pathway. These include chemical inducers, myogenic-enhancing cell culture substrates, and mechanical and dynamic culturing conditions. Drawing on information from embryonic and postnatal myogenesis from somites, satellite, and myogenic progenitor cells, the mechanisms behind the chemical and mechanical induction strategies can be studied, and the sequential gene and signaling cascades can be used to monitor the progression of myogenic differentiation in the laboratory. Increased understanding of the stimuli and signaling mechanisms in the initial stages of MSC myogenic commitment will provide tools with which we can enhance their differentiation efficacy and advance the process to clinical translation.
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Affiliation(s)
- Simone Grobbelaar
- Department of Physiology, School of Medicine, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
- Institute for Cellular and Molecular Medicine, Department of Immunology, and South African Medical Research Council Extramural Unit for Stem Cell Research and Therapy, School of Medicine, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
| | - Anne E. Mercier
- Department of Physiology, School of Medicine, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
| | - Iman van den Bout
- Department of Physiology, School of Medicine, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
- Centre for Neuroendocrinology, Department of Immunology, School of Medicine, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
| | - Chrisna Durandt
- Institute for Cellular and Molecular Medicine, Department of Immunology, and South African Medical Research Council Extramural Unit for Stem Cell Research and Therapy, School of Medicine, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
| | - Michael S. Pepper
- Institute for Cellular and Molecular Medicine, Department of Immunology, and South African Medical Research Council Extramural Unit for Stem Cell Research and Therapy, School of Medicine, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
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16
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Wang P, Liu X, Yao Z, Chen Y, Luo L, Liang K, Tan JHE, Chua MWJ, Chua YJB, Ma S, Zhang L, Ma W, Liu S, Cao W, Guo L, Guang L, Wang Y, Zhao H, Ai N, Li Y, Li C, Wang RR, Teh BT, Jiang L, Yu K, Shyh-Chang N. Lin28a maintains a subset of adult muscle stem cells in an embryonic-like state. Cell Res 2023; 33:712-726. [PMID: 37188880 PMCID: PMC10474071 DOI: 10.1038/s41422-023-00818-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 04/23/2023] [Indexed: 05/17/2023] Open
Abstract
During homeostasis and after injury, adult muscle stem cells (MuSCs) activate to mediate muscle regeneration. However, much remains unclear regarding the heterogeneous capacity of MuSCs for self-renewal and regeneration. Here, we show that Lin28a is expressed in embryonic limb bud muscle progenitors, and that a rare reserve subset of Lin28a+Pax7- skeletal MuSCs can respond to injury at adult stage by replenishing the Pax7+ MuSC pool to drive muscle regeneration. Compared with adult Pax7+ MuSCs, Lin28a+ MuSCs displayed enhanced myogenic potency in vitro and in vivo upon transplantation. The epigenome of adult Lin28a+ MuSCs showed resemblance to embryonic muscle progenitors. In addition, RNA-sequencing revealed that Lin28a+ MuSCs co-expressed higher levels of certain embryonic limb bud transcription factors, telomerase components and the p53 inhibitor Mdm4, and lower levels of myogenic differentiation markers compared to adult Pax7+ MuSCs, resulting in enhanced self-renewal and stress-response signatures. Functionally, conditional ablation and induction of Lin28a+ MuSCs in adult mice revealed that these cells are necessary and sufficient for efficient muscle regeneration. Together, our findings connect the embryonic factor Lin28a to adult stem cell self-renewal and juvenile regeneration.
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Affiliation(s)
- Peng Wang
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xupeng Liu
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ziyue Yao
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yu Chen
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Lanfang Luo
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Kun Liang
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jun-Hao Elwin Tan
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
- Institute of Molecular and Cell Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore
- Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore
| | - Min-Wen Jason Chua
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
- Institute of Molecular and Cell Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore
- Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore
| | - Yan-Jiang Benjamin Chua
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
- Institute of Molecular and Cell Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore
- Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore
| | - Shilin Ma
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Liping Zhang
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Wenwu Ma
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Shuqing Liu
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Wenhua Cao
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Luyao Guo
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Lu Guang
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yuefan Wang
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - He Zhao
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Na Ai
- University of Chinese Academy of Sciences, Beijing, China
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Yun Li
- University of Chinese Academy of Sciences, Beijing, China
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Chunwei Li
- Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ruiqi Rachel Wang
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Bin Tean Teh
- Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore
| | - Lan Jiang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Kang Yu
- Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ng Shyh-Chang
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
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17
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Wurmser M, Madani R, Chaverot N, Backer S, Borok M, Dos Santos M, Comai G, Tajbakhsh S, Relaix F, Santolini M, Sambasivan R, Jiang R, Maire P. Overlapping functions of SIX homeoproteins during embryonic myogenesis. PLoS Genet 2023; 19:e1010781. [PMID: 37267426 DOI: 10.1371/journal.pgen.1010781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 05/10/2023] [Indexed: 06/04/2023] Open
Abstract
Four SIX homeoproteins display a combinatorial expression throughout embryonic developmental myogenesis and they modulate the expression of the myogenic regulatory factors. Here, we provide a deep characterization of their role in distinct mouse developmental territories. We showed, at the hypaxial level, that the Six1:Six4 double knockout (dKO) somitic precursor cells adopt a smooth muscle fate and lose their myogenic identity. At the epaxial level, we demonstrated by the analysis of Six quadruple KO (qKO) embryos, that SIX are required for fetal myogenesis, and for the maintenance of PAX7+ progenitor cells, which differentiated prematurely and are lost by the end of fetal development in qKO embryos. Finally, we showed that Six1 and Six2 are required to establish craniofacial myogenesis by controlling the expression of Myf5. We have thus described an unknown role for SIX proteins in the control of myogenesis at different embryonic levels and refined their involvement in the genetic cascades operating at the head level and in the genesis of myogenic stem cells.
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Affiliation(s)
- Maud Wurmser
- Université de Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Rouba Madani
- Université de Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Nathalie Chaverot
- Université de Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Stéphanie Backer
- Université de Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Matthew Borok
- Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB, Creteil, France
| | | | - Glenda Comai
- Stem Cells & Development, Institut Pasteur, Paris, France
- CNRS UMR 3738, Institut Pasteur, Paris, France
| | - Shahragim Tajbakhsh
- Stem Cells & Development, Institut Pasteur, Paris, France
- CNRS UMR 3738, Institut Pasteur, Paris, France
| | - Frédéric Relaix
- Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB, Creteil, France
| | - Marc Santolini
- Université de Paris Cité, Interaction Data Lab, CRI Paris, INSERM. Paris, France
| | - Ramkumar Sambasivan
- Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati, Andhra Pradesh, India
| | - Rulang Jiang
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Pascal Maire
- Université de Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
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18
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Zhu S, Li W, Zhang H, Yan Y, Mei Q, Wu K. Retinal determination gene networks: from biological functions to therapeutic strategies. Biomark Res 2023; 11:18. [PMID: 36750914 PMCID: PMC9906957 DOI: 10.1186/s40364-023-00459-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 01/28/2023] [Indexed: 02/09/2023] Open
Abstract
The retinal determinant gene network (RDGN), originally discovered as a critical determinator in Drosophila eye specification, has become an important regulatory network in tumorigenesis and progression, as well as organogenesis. This network is not only associated with malignant biological behaviors of tumors, such as proliferation, and invasion, but also regulates the development of multiple mammalian organs. Three members of this conservative network have been extensively investigated, including DACH, SIX, and EYA. Dysregulated RDGN signaling is associated with the initiation and progression of tumors. In recent years, it has been found that the members of this network can be used as prognostic markers for cancer patients. Moreover, they are considered to be potential therapeutic targets for cancer. Here, we summarize the research progress of RDGN members from biological functions to signaling transduction, especially emphasizing their effects on tumors. Additionally, we discuss the roles of RDGN members in the development of organs and tissue as well as their correlations with the pathogenesis of chronic kidney disease and coronary heart disease. By summarizing the roles of RDGN members in human diseases, we hope to promote future investigations into RDGN and provide potential therapeutic strategies for patients.
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Affiliation(s)
- Shuangli Zhu
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Wanling Li
- grid.412793.a0000 0004 1799 5032Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China ,grid.470966.aCancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032 China
| | - Hao Zhang
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Yuheng Yan
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Qi Mei
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China. .,Cancer Center, Tongji hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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19
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Yaman YI, Ramanathan S. Controlling human organoid symmetry breaking reveals signaling gradients drive segmentation clock waves. Cell 2023; 186:513-527.e19. [PMID: 36657441 PMCID: PMC10025047 DOI: 10.1016/j.cell.2022.12.042] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/29/2022] [Accepted: 12/21/2022] [Indexed: 01/19/2023]
Abstract
Axial development of mammals involves coordinated morphogenetic events, including axial elongation, somitogenesis, and neural tube formation. To gain insight into the signals controlling the dynamics of human axial morphogenesis, we generated axially elongating organoids by inducing anteroposterior symmetry breaking of spatially coupled epithelial cysts derived from human pluripotent stem cells. Each organoid was composed of a neural tube flanked by presomitic mesoderm sequentially segmented into somites. Periodic activation of the somite differentiation gene MESP2 coincided in space and time with anteriorly traveling segmentation clock waves in the presomitic mesoderm of the organoids, recapitulating critical aspects of somitogenesis. Timed perturbations demonstrated that FGF and WNT signaling play distinct roles in axial elongation and somitogenesis, and that FGF signaling gradients drive segmentation clock waves. By generating and perturbing organoids that robustly recapitulate the architecture of multiple axial tissues in human embryos, this work offers a means to dissect mechanisms underlying human embryogenesis.
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Affiliation(s)
- Yusuf Ilker Yaman
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
| | - Sharad Ramanathan
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
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20
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Kahsay A, Rodriguez-Marquez E, López-Pérez A, Hörnblad A, von Hofsten J. Pax3 loss of function delays tumour progression in kRAS-induced zebrafish rhabdomyosarcoma models. Sci Rep 2022; 12:17149. [PMID: 36229514 PMCID: PMC9561152 DOI: 10.1038/s41598-022-21525-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/28/2022] [Indexed: 01/04/2023] Open
Abstract
Rhabdomyosarcoma is a soft tissue cancer that arises in skeletal muscle due to mutations in myogenic progenitors that lead to ineffective differentiation and malignant transformation. The transcription factors Pax3 and Pax7 and their downstream target genes are tightly linked with the fusion positive alveolar subtype, whereas the RAS pathway is usually involved in the embryonal, fusion negative variant. Here, we analyse the role of Pax3 in a fusion negative context, by linking alterations in gene expression in pax3a/pax3b double mutant zebrafish with tumour progression in kRAS-induced rhabdomyosarcoma tumours. Several genes in the RAS/MAPK signalling pathway were significantly down-regulated in pax3a/pax3b double mutant zebrafish. Progression of rhabdomyosarcoma tumours was also delayed in the pax3a/pax3b double mutant zebrafish indicating that Pax3 transcription factors have an unappreciated role in mediating malignancy in fusion negative rhabdomyosarcoma.
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Affiliation(s)
- A. Kahsay
- grid.12650.300000 0001 1034 3451Integrative Medical Biology (IMB), Umeå University, Johan Bures Väg 12, 90187 Umeå, Sweden
| | - E. Rodriguez-Marquez
- grid.12650.300000 0001 1034 3451Integrative Medical Biology (IMB), Umeå University, Johan Bures Väg 12, 90187 Umeå, Sweden
| | - A. López-Pérez
- grid.12650.300000 0001 1034 3451Umeå Centre for Molecular Medicine (UCMM), Umeå University, Johan Bures Väg 12, 90187 Umeå, Sweden
| | - A. Hörnblad
- grid.12650.300000 0001 1034 3451Umeå Centre for Molecular Medicine (UCMM), Umeå University, Johan Bures Väg 12, 90187 Umeå, Sweden
| | - J. von Hofsten
- grid.12650.300000 0001 1034 3451Integrative Medical Biology (IMB), Umeå University, Johan Bures Väg 12, 90187 Umeå, Sweden
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21
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Khabyuk J, Pröls F, Draga M, Scaal M. Development of ribs and intercostal muscles in the chicken embryo. J Anat 2022; 241:831-845. [PMID: 35751554 PMCID: PMC9358761 DOI: 10.1111/joa.13716] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/06/2022] [Accepted: 06/06/2022] [Indexed: 11/27/2022] Open
Abstract
In the thorax of higher vertebrates, ribs and intercostal muscles play a decisive role in stability and respiratory movements of the body wall. They are derivatives of the somites, the ribs originating in the sclerotome and the intercostal muscles originating in the myotome. During thorax development, ribs and intercostal muscles extend into the lateral plate mesoderm and eventually contact the sternum during ventral closure. Here, we give a detailed description of the morphogenesis of ribs and thoracic muscles in the chicken embryo (Gallus gallus). Using Alcian blue staining as well as Sox9 and Desmin whole‐mount immunohistochemistry, we monitor synchronously the development of rib cartilage and intercostal muscle anlagen. We show that the muscle anlagen precede the rib anlagen during ventrolateral extension, which is in line with the inductive role of the myotome in rib differentiation. Our studies furthermore reveal the temporary formation of a previously unknown eighth rib in the chicken embryonic thorax.
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Affiliation(s)
- Julia Khabyuk
- Faculty of Medicine and University Hospital Cologne, Center of Anatomy, University of Cologne, Cologne, Germany
| | - Felicitas Pröls
- Faculty of Medicine and University Hospital Cologne, Center of Anatomy, University of Cologne, Cologne, Germany
| | - Margarethe Draga
- Faculty of Medicine and University Hospital Cologne, Center of Anatomy, University of Cologne, Cologne, Germany
| | - Martin Scaal
- Faculty of Medicine and University Hospital Cologne, Center of Anatomy, University of Cologne, Cologne, Germany
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22
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Hsu JY, Danis EP, Nance S, O'Brien JH, Gustafson AL, Wessells VM, Goodspeed AE, Talbot JC, Amacher SL, Jedlicka P, Black JC, Costello JC, Durbin AD, Artinger KB, Ford HL. SIX1 reprograms myogenic transcription factors to maintain the rhabdomyosarcoma undifferentiated state. Cell Rep 2022; 38:110323. [PMID: 35108532 PMCID: PMC8917510 DOI: 10.1016/j.celrep.2022.110323] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 10/21/2021] [Accepted: 01/10/2022] [Indexed: 12/13/2022] Open
Abstract
Rhabdomyosarcoma (RMS) is a pediatric muscle sarcoma characterized by expression of the myogenic lineage transcription factors (TFs) MYOD1 and MYOG. Despite high expression of these TFs, RMS cells fail to terminally differentiate, suggesting the presence of factors that alter their functions. Here, we demonstrate that the developmental TF SIX1 is highly expressed in RMS and critical for maintaining a muscle progenitor-like state. SIX1 loss induces differentiation of RMS cells into myotube-like cells and impedes tumor growth in vivo. We show that SIX1 maintains the RMS undifferentiated state by controlling enhancer activity and MYOD1 occupancy at loci more permissive to tumor growth over muscle differentiation. Finally, we demonstrate that a gene signature derived from SIX1 loss correlates with differentiation status and predicts RMS progression in human disease. Our findings demonstrate a master regulatory role of SIX1 in repression of RMS differentiation via genome-wide alterations in MYOD1 and MYOG-mediated transcription.
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Affiliation(s)
- Jessica Y Hsu
- Department of Pharmacology, University of Colorado Anschutz Medical Campus (UC-AMC), Aurora, CO, USA; Pharmacology Graduate Program, UC-AMC, Aurora, CO, USA
| | - Etienne P Danis
- Department of Pharmacology, University of Colorado Anschutz Medical Campus (UC-AMC), Aurora, CO, USA; University of Colorado Cancer Center, UC-AMC, Aurora, CO, USA
| | - Stephanie Nance
- Division of Molecular Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jenean H O'Brien
- Department of Biology, College of St. Scholastica, Duluth, MN, USA
| | - Annika L Gustafson
- Department of Pharmacology, University of Colorado Anschutz Medical Campus (UC-AMC), Aurora, CO, USA; Molecular Biology Graduate Program, UC-AMC, Aurora, CO, USA
| | | | - Andrew E Goodspeed
- Department of Pharmacology, University of Colorado Anschutz Medical Campus (UC-AMC), Aurora, CO, USA; University of Colorado Cancer Center, UC-AMC, Aurora, CO, USA
| | - Jared C Talbot
- School of Biology and Ecology, University of Maine, Orono, ME, USA
| | - Sharon L Amacher
- Department of Molecular Genetics, Ohio State University, Columbus, OH, USA
| | | | - Joshua C Black
- Department of Pharmacology, University of Colorado Anschutz Medical Campus (UC-AMC), Aurora, CO, USA; Pharmacology Graduate Program, UC-AMC, Aurora, CO, USA
| | - James C Costello
- Department of Pharmacology, University of Colorado Anschutz Medical Campus (UC-AMC), Aurora, CO, USA; Pharmacology Graduate Program, UC-AMC, Aurora, CO, USA; University of Colorado Cancer Center, UC-AMC, Aurora, CO, USA
| | - Adam D Durbin
- Division of Molecular Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Kristin B Artinger
- Department of Craniofacial Biology, UC-AMC, Aurora, CO, USA; University of Colorado Cancer Center, UC-AMC, Aurora, CO, USA.
| | - Heide L Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus (UC-AMC), Aurora, CO, USA; Pharmacology Graduate Program, UC-AMC, Aurora, CO, USA; University of Colorado Cancer Center, UC-AMC, Aurora, CO, USA.
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23
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Della Gaspera B, Weill L, Chanoine C. Evolution of Somite Compartmentalization: A View From Xenopus. Front Cell Dev Biol 2022; 9:790847. [PMID: 35111756 PMCID: PMC8802780 DOI: 10.3389/fcell.2021.790847] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/26/2021] [Indexed: 11/13/2022] Open
Abstract
Somites are transitory metameric structures at the basis of the axial organization of vertebrate musculoskeletal system. During evolution, somites appear in the chordate phylum and compartmentalize mainly into the dermomyotome, the myotome, and the sclerotome in vertebrates. In this review, we summarized the existing literature about somite compartmentalization in Xenopus and compared it with other anamniote and amniote vertebrates. We also present and discuss a model that describes the evolutionary history of somite compartmentalization from ancestral chordates to amniote vertebrates. We propose that the ancestral organization of chordate somite, subdivided into a lateral compartment of multipotent somitic cells (MSCs) and a medial primitive myotome, evolves through two major transitions. From ancestral chordates to vertebrates, the cell potency of MSCs may have evolved and gave rise to all new vertebrate compartments, i.e., the dermomyome, its hypaxial region, and the sclerotome. From anamniote to amniote vertebrates, the lateral MSC territory may expand to the whole somite at the expense of primitive myotome and may probably facilitate sclerotome formation. We propose that successive modifications of the cell potency of some type of embryonic progenitors could be one of major processes of the vertebrate evolution.
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24
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Coppenrath K, Tavares ALP, Shaidani NI, Wlizla M, Moody SA, Horb M. Generation of a new six1-null line in Xenopus tropicalis for study of development and congenital disease. Genesis 2021; 59:e23453. [PMID: 34664392 DOI: 10.1002/dvg.23453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/02/2021] [Accepted: 09/04/2021] [Indexed: 12/15/2022]
Abstract
The vertebrate Six (Sine oculis homeobox) family of homeodomain transcription factors plays critical roles in the development of several organs. Six1 plays a central role in cranial placode development, including the precursor tissues of the inner ear, as well as other cranial sensory organs and the kidney. In humans, mutations in SIX1 underlie some cases of Branchio-oto-renal (BOR) syndrome, which is characterized by moderate-to-severe hearing loss. We utilized CRISPR/Cas9 technology to establish a six1 mutant line in Xenopus tropicalis that is available to the research community. We demonstrate that at larval stages, the six1-null animals show severe disruptions in gene expression of putative Six1 target genes in the otic vesicle, cranial ganglia, branchial arch, and neural tube. At tadpole stages, six1-null animals display dysmorphic Meckel's, ceratohyal, and otic capsule cartilage morphology. This mutant line will be of value for the study of the development of several organs as well as congenital syndromes that involve these tissues.
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Affiliation(s)
- Kelsey Coppenrath
- Eugene Bell Center for Regenerative Biology and Tissue Engineering and National Xenopus Resource, Marine Biological Laboratory, Woods Hole, Massachusetts, USA
| | - Andre L P Tavares
- Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Nikko-Ideen Shaidani
- Eugene Bell Center for Regenerative Biology and Tissue Engineering and National Xenopus Resource, Marine Biological Laboratory, Woods Hole, Massachusetts, USA
| | - Marcin Wlizla
- Eugene Bell Center for Regenerative Biology and Tissue Engineering and National Xenopus Resource, Marine Biological Laboratory, Woods Hole, Massachusetts, USA.,Embryology Department, Charles River Laboratories, Wilmington, Massachusetts, USA
| | - Sally A Moody
- Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Marko Horb
- Eugene Bell Center for Regenerative Biology and Tissue Engineering and National Xenopus Resource, Marine Biological Laboratory, Woods Hole, Massachusetts, USA
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25
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Matured Myofibers in Bioprinted Constructs with In Vivo Vascularization and Innervation. Gels 2021; 7:gels7040171. [PMID: 34698150 PMCID: PMC8544540 DOI: 10.3390/gels7040171] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/03/2021] [Accepted: 10/11/2021] [Indexed: 01/08/2023] Open
Abstract
For decades, the study of tissue-engineered skeletal muscle has been driven by a clinical need to treat neuromuscular diseases and volumetric muscle loss. The in vitro fabrication of muscle offers the opportunity to test drug-and cell-based therapies, to study disease processes, and to perhaps, one day, serve as a muscle graft for reconstructive surgery. This study developed a biofabrication technique to engineer muscle for research and clinical applications. A bioprinting protocol was established to deliver primary mouse myoblasts in a gelatin methacryloyl (GelMA) bioink, which was implanted in an in vivo chamber in a nude rat model. For the first time, this work demonstrated the phenomenon of myoblast migration through the bioprinted GelMA scaffold with cells spontaneously forming fibers on the surface of the material. This enabled advanced maturation and facilitated the connection between incoming vessels and nerve axons in vivo without the hindrance of a scaffold material. Immunohistochemistry revealed the hallmarks of tissue maturity with sarcomeric striations and peripherally placed nuclei in the organized bundles of muscle fibers. Such engineered muscle autografts could, with further structural development, eventually be used for surgical reconstructive purposes while the methodology presented here specifically has wide applications for in vitro and in vivo neuromuscular function and disease modelling.
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26
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Esteves de Lima J, Relaix F. Master regulators of skeletal muscle lineage development and pluripotent stem cells differentiation. CELL REGENERATION 2021; 10:31. [PMID: 34595600 PMCID: PMC8484369 DOI: 10.1186/s13619-021-00093-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/24/2021] [Indexed: 12/16/2022]
Abstract
In vertebrates, the skeletal muscles of the body and their associated stem cells originate from muscle progenitor cells, during development. The specification of the muscles of the trunk, head and limbs, relies on the activity of distinct genetic hierarchies. The major regulators of trunk and limb muscle specification are the paired-homeobox transcription factors PAX3 and PAX7. Distinct gene regulatory networks drive the formation of the different muscles of the head. Despite the redeployment of diverse upstream regulators of muscle progenitor differentiation, the commitment towards the myogenic fate requires the expression of the early myogenic regulatory factors MYF5, MRF4, MYOD and the late differentiation marker MYOG. The expression of these genes is activated by muscle progenitors throughout development, in several waves of myogenic differentiation, constituting the embryonic, fetal and postnatal phases of muscle growth. In order to achieve myogenic cell commitment while maintaining an undifferentiated pool of muscle progenitors, several signaling pathways regulate the switch between proliferation and differentiation of myoblasts. The identification of the gene regulatory networks operating during myogenesis is crucial for the development of in vitro protocols to differentiate pluripotent stem cells into myoblasts required for regenerative medicine.
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Affiliation(s)
| | - Frédéric Relaix
- Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB, 94010, Creteil, France.
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27
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Qiao J, Wang S, Zhou J, Tan B, Li Z, Zheng E, Cai G, Wu Z, Hong L, Gu T. ITGB6 inhibits the proliferation of porcine skeletal muscle satellite cells. Cell Biol Int 2021; 46:96-105. [PMID: 34519117 DOI: 10.1002/cbin.11702] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/30/2021] [Accepted: 09/12/2021] [Indexed: 01/17/2023]
Abstract
The formation of embryonic muscle fibers determines the amount of postnatal muscles and is regulated by a variety of signaling pathways and transcription factors. Previously, by using chromatin immunoprecipitation-sequencing and RNA-Seq techniques, we identified a large number of genes that are regulated by H3K27me3 in porcine embryonic skeletal muscles. Among these genes, we found that ITGB6 is regulated by H3K27me3. However, its function in muscle development is unknown. In this study, we first verified that ITGB6 was differentially regulated by H3K27me3 and that its expression levels were upregulated in porcine skeletal muscles at embryonic Days 33, 65, and 90. Then, we performed gain- or loss-of-function studies on porcine skeletal muscle satellite cells to study the role of ITGB6 in porcine skeletal muscle development. The proliferation of porcine skeletal muscle satellite cells was studied through real-time polymerase chain reaction, Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining, Western blot, and flow cytometry analyses. We found that the ITGB6 gene was regulated by H3K27me3 during muscle development and had an inhibitory effect on the proliferation of porcine skeletal muscle satellite cells.
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Affiliation(s)
- Jiaxin Qiao
- Department of Animal Genetics, Breeding, and Reproduction, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Shanshan Wang
- Department of Animal Genetics, Breeding, and Reproduction, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Jian Zhou
- Department of Animal Genetics, Breeding, and Reproduction, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Baohua Tan
- Department of Animal Genetics, Breeding, and Reproduction, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Zicong Li
- Department of Animal Genetics, Breeding, and Reproduction, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangzhou, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, Guangzhou, China.,Guangdong Wens Breeding Swine Technology Co., Ltd., Yunfu, China
| | - Enqin Zheng
- Department of Animal Genetics, Breeding, and Reproduction, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Gengyuan Cai
- Department of Animal Genetics, Breeding, and Reproduction, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China.,Guangdong Wens Breeding Swine Technology Co., Ltd., Yunfu, China
| | - Zhenfang Wu
- Department of Animal Genetics, Breeding, and Reproduction, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangzhou, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, Guangzhou, China.,Guangdong Wens Breeding Swine Technology Co., Ltd., Yunfu, China
| | - Linjun Hong
- Department of Animal Genetics, Breeding, and Reproduction, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Ting Gu
- Department of Animal Genetics, Breeding, and Reproduction, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
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28
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Meurer L, Ferdman L, Belcher B, Camarata T. The SIX Family of Transcription Factors: Common Themes Integrating Developmental and Cancer Biology. Front Cell Dev Biol 2021; 9:707854. [PMID: 34490256 PMCID: PMC8417317 DOI: 10.3389/fcell.2021.707854] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 06/28/2021] [Indexed: 01/19/2023] Open
Abstract
The sine oculis (SIX) family of transcription factors are key regulators of developmental processes during embryogenesis. Members of this family control gene expression to promote self-renewal of progenitor cell populations and govern mechanisms of cell differentiation. When the function of SIX genes becomes disrupted, distinct congenital defects develops both in animal models and humans. In addition to the embryonic setting, members of the SIX family have been found to be critical regulators of tumorigenesis, promoting cell proliferation, epithelial-to-mesenchymal transition, and metastasis. Research in both the fields of developmental biology and cancer research have provided an extensive understanding of SIX family transcription factor functions. Here we review recent progress in elucidating the role of SIX family genes in congenital disease as well as in the promotion of cancer. Common themes arise when comparing SIX transcription factor function during embryonic and cancer development. We highlight the complementary nature of these two fields and how knowledge in one area can open new aspects of experimentation in the other.
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Affiliation(s)
- Logan Meurer
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
| | - Leonard Ferdman
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
| | - Beau Belcher
- Department of Biological Sciences, Arkansas State University, Jonesboro, AR, United States
| | - Troy Camarata
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
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29
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Kostyuk SV, Proskurnina EV, Ershova ES, Kameneva LV, Malinovskaya EM, Savinova EA, Sergeeva VA, Umriukhin PE, Dolgikh OA, Khakina EA, Kraevaya OA, Troshin PA, Kutsev SI, Veiko NN. The Phosphonate Derivative of C 60 Fullerene Induces Differentiation towards the Myogenic Lineage in Human Adipose-Derived Mesenchymal Stem Cells. Int J Mol Sci 2021; 22:ijms22179284. [PMID: 34502190 PMCID: PMC8431706 DOI: 10.3390/ijms22179284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/19/2021] [Accepted: 08/25/2021] [Indexed: 12/26/2022] Open
Abstract
Inductors of myogenic stem cell differentiation attract attention, as they can be used to treat myodystrophies and post-traumatic injuries. Functionalization of fullerenes makes it possible to obtain water-soluble derivatives with targeted biochemical activity. This study examined the effects of the phosphonate C60 fullerene derivatives on the expression of myogenic transcription factors and myogenic differentiation of human mesenchymal stem cells (MSCs). Uptake of the phosphonate C60 fullerene derivatives in human MSCs, intracellular ROS visualization, superoxide scavenging potential, and the expression of myogenic, adipogenic, and osteogenic differentiation genes were studied. The prolonged MSC incubation (within 7–14 days) with the C60 pentaphoshonate potassium salt promoted their differentiation towards the myogenic lineage. The transcription factors and gene expressions determining myogenic differentiation (MYOD1, MYOG, MYF5, and MRF4) increased, while the expression of osteogenic differentiation factors (BMP2, BMP4, RUNX2, SPP1, and OCN) and adipogenic differentiation factors (CEBPB, LPL, and AP2 (FABP4)) was reduced or did not change. The stimulation of autophagy may be one of the factors contributing to the increased expression of myogenic differentiation genes in MSCs. Autophagy may be caused by intracellular alkalosis and/or short-term intracellular oxidative stress.
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Affiliation(s)
- Svetlana V. Kostyuk
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
| | - Elena V. Proskurnina
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
- Correspondence:
| | - Elizaveta S. Ershova
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
| | - Larisa V. Kameneva
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
| | - Elena M. Malinovskaya
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
| | - Ekaterina A. Savinova
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
| | - Vasilina A. Sergeeva
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
| | - Pavel E. Umriukhin
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
- Department of Normal Physiology, I.M. Sechenov First Moscow State Medical University (Sechenov University) , Mohovaya Str. 11-4, 125009 Moscow, Russia
| | - Olga A. Dolgikh
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
| | - Ekaterina A. Khakina
- A.N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, Vavylova St. 28, B-334, 119991 Moscow, Russia;
| | - Olga A. Kraevaya
- Institute of Problems of Chemical Physics of Russian Academy of Sciences, Semenov Prospect 1, 142432 Chernogolovka (Moscow Region), Russia; (O.A.K.); (P.A.T.)
| | - Pavel A. Troshin
- Institute of Problems of Chemical Physics of Russian Academy of Sciences, Semenov Prospect 1, 142432 Chernogolovka (Moscow Region), Russia; (O.A.K.); (P.A.T.)
| | - Sergey I. Kutsev
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
| | - Natalia N. Veiko
- Research Centre for Medical Genetics, ul. Moskvorechye 1, 115522 Moscow, Russia; (S.V.K.); (E.S.E.); (L.V.K.); (E.M.M.); (E.A.S.); (V.A.S.); (P.E.U.); (O.A.D.); (S.I.K.); (N.N.V.)
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30
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Nord H, Kahsay A, Dennhag N, Pedrosa Domellöf F, von Hofsten J. Genetic compensation between Pax3 and Pax7 in zebrafish appendicular muscle formation. Dev Dyn 2021; 251:1423-1438. [PMID: 34435397 DOI: 10.1002/dvdy.415] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 08/18/2021] [Accepted: 08/18/2021] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Migrating muscle progenitors delaminate from the somite and subsequently form muscle tissue in distant anatomical regions such as the paired appendages, or limbs. In amniotes, this process requires a signaling cascade including the transcription factor paired box 3 (Pax3). RESULTS In this study, we found that, unlike in mammals, pax3a/3b double mutant zebrafish develop near to normal appendicular muscle. By analyzing numerous mutant combinations of pax3a, pax3b and pax7a, and pax7b, we determined that there is a feedback system and a compensatory mechanism between Pax3 and Pax7 in this developmental process, even though Pax7 alone is not required for appendicular myogenesis. pax3a/3b/7a/7b quadruple mutant developed muscle-less pectoral fins. CONCLUSIONS We found that Pax3 and Pax7 are redundantly required during appendicular myogenesis in zebrafish, where Pax7 is able to activate the same developmental programs as Pax3 in the premigratory progenitor cells.
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Affiliation(s)
- Hanna Nord
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Abraha Kahsay
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Nils Dennhag
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Fatima Pedrosa Domellöf
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.,Department of Clinical Science, Ophthalmology, Umeå University, Umeå, Sweden
| | - Jonas von Hofsten
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
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From Bipotent Neuromesodermal Progenitors to Neural-Mesodermal Interactions during Embryonic Development. Int J Mol Sci 2021; 22:ijms22179141. [PMID: 34502050 PMCID: PMC8431582 DOI: 10.3390/ijms22179141] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/22/2021] [Accepted: 08/23/2021] [Indexed: 11/17/2022] Open
Abstract
To ensure the formation of a properly patterned embryo, multiple processes must operate harmoniously at sequential phases of development. This is implemented by mutual interactions between cells and tissues that together regulate the segregation and specification of cells, their growth and morphogenesis. The formation of the spinal cord and paraxial mesoderm derivatives exquisitely illustrate these processes. Following early gastrulation, while the vertebrate body elongates, a population of bipotent neuromesodermal progenitors resident in the posterior region of the embryo generate both neural and mesodermal lineages. At later stages, the somitic mesoderm regulates aspects of neural patterning and differentiation of both central and peripheral neural progenitors. Reciprocally, neural precursors influence the paraxial mesoderm to regulate somite-derived myogenesis and additional processes by distinct mechanisms. Central to this crosstalk is the activity of the axial notochord, which, via sonic hedgehog signaling, plays pivotal roles in neural, skeletal muscle and cartilage ontogeny. Here, we discuss the cellular and molecular basis underlying this complex developmental plan, with a focus on the logic of sonic hedgehog activities in the coordination of the neural-mesodermal axis.
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32
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Skrzypek K, Adamek G, Kot M, Badyra B, Majka M. Progression and Differentiation of Alveolar Rhabdomyosarcoma Is Regulated by PAX7 Transcription Factor-Significance of Tumor Subclones. Cells 2021; 10:1870. [PMID: 34440639 PMCID: PMC8391953 DOI: 10.3390/cells10081870] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/12/2021] [Accepted: 07/20/2021] [Indexed: 12/15/2022] Open
Abstract
Rhabdomyosarcoma (RMS), is the most frequent soft tissue tumor in children that originates from disturbances in differentiation process. Mechanisms leading to the development of RMS are still poorly understood. Therefore, by analysis of two RMS RH30 cell line subclones, one subclone PAX7 negative, while the second one PAX7 positive, and comparison with other RMS cell lines we aimed at identifying new mechanisms crucial for RMS progression. RH30 subclones were characterized by the same STR profile, but different morphology, rate of proliferation, migration activity and chemotactic abilities in vitro, as well as differences in tumor morphology and growth in vivo. Our analysis indicated a different level of expression of adhesion molecules (e.g., from VLA and ICAM families), myogenic microRNAs, such as miR-206 and transcription factors, such as MYOD, MYOG, SIX1, and ID. Silencing of PAX7 transcription factor with siRNA confirmed the crucial role of PAX7 transcription factor in proliferation, differentiation and migration of RMS cells. To conclude, our results suggest that tumor cell lines with the same STR profile can produce subclones that differ in many features and indicate crucial roles of PAX7 and ID proteins in the development of RMS.
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Affiliation(s)
| | | | | | | | - Marcin Majka
- Department of Transplantation, Faculty of Medicine, Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland; (G.A.); (M.K.); (B.B.)
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33
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Effects of maternal gestational diet, with or without methionine, on muscle transcriptome of Bos indicus-influenced beef calves following a vaccine-induced immunological challenge. PLoS One 2021; 16:e0253810. [PMID: 34166453 PMCID: PMC8224847 DOI: 10.1371/journal.pone.0253810] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/11/2021] [Indexed: 12/13/2022] Open
Abstract
Maternal nutrition during gestation can cause epigenetic effects that translate to alterations in gene expression in offspring. This 2-year study employed RNA-sequencing technology to evaluate the pre- and post-vaccination muscle transcriptome of early-weaned Bos indicus-influenced beef calves born from dams offered different supplementation strategies from 57 ± 5 d prepartum until 17 ± 5 d postpartum. Seventy-two Brangus heifers (36 heifers/yr) were stratified by body weight and body condition score and assigned to bahiagrass pastures (3 heifers/pasture/yr). Treatments were randomly assigned to pastures and consisted of (i) no pre- or postpartum supplementation (NOSUP), (ii) pre- and postpartum supplementation of protein and energy using 7.2 kg of dry matter/heifer/wk of molasses + urea (MOL), or (iii) MOL fortified with 105 g/heifer/wk of methionine hydroxy analog (MOLMET). Calves were weaned on d 147 of the study. On d 154, 24 calves/yr (8 calves/treatment) were randomly selected and individually limit-fed a high-concentrate diet until d 201. Calves were vaccinated on d 160. Muscle biopsies were collected from the same calves (4 calves/treatment/day/yr) on d 154 (pre-vaccination) and 201 (post-vaccination) for gene expression analysis using RNA sequencing. Molasses maternal supplementation led to a downregulation of genes associated with muscle cell differentiation and development along with intracellular signaling pathways (e.g., Wnt and TGF-β signaling pathway) compared to no maternal supplementation. Maternal fortification with methionine altered functional gene-sets involved in amino acid transport and metabolism and the one-carbon cycle. In addition, muscle transcriptome was impacted by vaccination with a total of 2,396 differentially expressed genes (FDR ≤ 0.05) on d 201 vs. d 154. Genes involved in cell cycle progression, extracellular matrix, and collagen formation were upregulated after vaccination. This study demonstrated that maternal supplementation of energy and protein, with or without, methionine has long-term implications on the muscle transcriptome of offspring and potentially influence postnatal muscle development.
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34
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Andrikou C, Hejnol A. FGF signaling acts on different levels of mesoderm development within Spiralia. Development 2021; 148:264929. [PMID: 33999997 PMCID: PMC8180254 DOI: 10.1242/dev.196089] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 04/08/2021] [Indexed: 01/23/2023]
Abstract
FGF signaling is involved in mesoderm induction in members of deuterostomes (e.g. tunicates, hemichordates), but not in flies and nematodes, in which it has a role in mesoderm patterning and migration. However, we need comparable studies in other protostome taxa in order to decipher whether this mesoderm-inducing function of FGF extends beyond the lineage of deuterostomes. Here, we investigated the role of FGF signaling in mesoderm development in three species of lophophorates, a clade within the protostome group Spiralia. Our gene expression analyses show that the mesodermal molecular patterning is conserved between brachiopods and phoronids, but the spatial and temporal recruitment of transcription factors differs significantly. Moreover, the use of the inhibitor SU5402 demonstrates that FGF signaling is involved in different steps of mesoderm development, as well as in morphogenetic movements of gastrulation and axial elongation. Our findings suggest that the mesoderm-inducing role of FGF extends beyond the group of deuterostomes.
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Affiliation(s)
- Carmen Andrikou
- University of Bergen, Department of Biological Sciences, Thormøhlensgate 55, 5006 Bergen, Norway.,Sars International Centre for Marine Molecular Biology, University of Bergen, Thormøhlensgate 55, 5006 Bergen, Norway
| | - Andreas Hejnol
- University of Bergen, Department of Biological Sciences, Thormøhlensgate 55, 5006 Bergen, Norway.,Sars International Centre for Marine Molecular Biology, University of Bergen, Thormøhlensgate 55, 5006 Bergen, Norway
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35
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Grifone R, Saquet A, Desgres M, Sangiorgi C, Gargano C, Li Z, Coletti D, Shi DL. Rbm24 displays dynamic functions required for myogenic differentiation during muscle regeneration. Sci Rep 2021; 11:9423. [PMID: 33941806 PMCID: PMC8093301 DOI: 10.1038/s41598-021-88563-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 04/06/2021] [Indexed: 01/01/2023] Open
Abstract
Skeletal muscle has a remarkable capacity of regeneration after injury, but the regulatory network underlying this repair process remains elusive. RNA-binding proteins play key roles in the post-transcriptional regulation of gene expression and the maintenance of tissue homeostasis and plasticity. Rbm24 regulates myogenic differentiation during early development, but its implication in adult muscle is poorly understood. Here we show that it exerts multiple functions in muscle regeneration. Consistent with its dynamic subcellular localization during embryonic muscle development, Rbm24 also displays cytoplasm to nucleus translocation during C2C12 myoblast differentiation. In adult mice, Rbm24 mRNA is enriched in slow-twitch muscles along with myogenin mRNA. The protein displays nuclear localization in both slow and fast myofibers. Upon injury, Rbm24 is rapidly upregulated in regenerating myofibers and accumulates in the myonucleus of nascent myofibers. Through satellite cell transplantation, we demonstrate that Rbm24 functions sequentially to regulate myogenic differentiation and muscle regeneration. It is required for myogenin expression at early stages of muscle injury and for muscle-specific pre-mRNA alternative splicing at late stages of regeneration. These results identify Rbm24 as a multifaceted regulator of myoblast differentiation. They provide insights into the molecular pathway orchestrating the expression of myogenic factors and muscle functional proteins during regeneration.
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Affiliation(s)
- Raphaëlle Grifone
- Laboratory of Developmental Biology (LBD), CNRS UMR7622, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 75005, Paris, France.
| | - Audrey Saquet
- Laboratory of Developmental Biology (LBD), CNRS UMR7622, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 75005, Paris, France
| | - Manon Desgres
- Laboratory of Developmental Biology (LBD), CNRS UMR7622, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 75005, Paris, France
| | - Claudia Sangiorgi
- Biological Adaptation and Ageing (B2A), CNRS UMR8256 and INSERM U1164, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 75005, Paris, France
| | - Caterina Gargano
- Biological Adaptation and Ageing (B2A), CNRS UMR8256 and INSERM U1164, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 75005, Paris, France
| | - Zhenlin Li
- Biological Adaptation and Ageing (B2A), CNRS UMR8256 and INSERM U1164, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 75005, Paris, France
| | - Dario Coletti
- Biological Adaptation and Ageing (B2A), CNRS UMR8256 and INSERM U1164, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 75005, Paris, France.,Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Histology and Medical Embryology Section, Sapienza University of Rome, 00161, Rome, Italy
| | - De-Li Shi
- Laboratory of Developmental Biology (LBD), CNRS UMR7622, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 75005, Paris, France.
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36
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Esteves de Lima J, Bou Akar R, Mansour M, Rocancourt D, Buckingham M, Relaix F. M-Cadherin Is a PAX3 Target During Myotome Patterning. Front Cell Dev Biol 2021; 9:652652. [PMID: 33869209 PMCID: PMC8047199 DOI: 10.3389/fcell.2021.652652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/12/2021] [Indexed: 11/13/2022] Open
Abstract
PAX3 belongs to the paired-homeobox family of transcription factors and plays a key role as an upstream regulator of muscle progenitor cells during embryonic development. Pax3-mutant embryos display impaired somite development, yet the consequences for myotome formation have not been characterized. The early myotome is formed by PAX3-expressing myogenic cells that delaminate from the dermomyotomal lips and migrate between the dermomyotome and sclerotome where they terminally differentiate. Here we show that in Pax3-mutant embryos, myotome formation is impaired, displays a defective basal lamina and the regionalization of the structural protein Desmin is lost. In addition, this phenotype is more severe in embryos combining Pax3-null and Pax3 dominant-negative alleles. We identify the adhesion molecule M-Cadherin as a PAX3 target gene, the expression of which is modulated in the myotome according to Pax3 gain- and loss-of-function alleles analyzed. Taken together, we identify M-Cadherin as a PAX3-target linked to the formation of the myotome.
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Affiliation(s)
- Joana Esteves de Lima
- Univ Paris Est Creteil, Institut National de la Santé et de la Recherche Médicale (INSERM), EnvA, Etablissement Français du Sang (EFS), Assistance Publique Hopitaux de Paris (AP-HP), Institut Mondor de Recherche Biomedicale (IMRB), Creteil, France
| | - Reem Bou Akar
- Univ Paris Est Creteil, Institut National de la Santé et de la Recherche Médicale (INSERM), EnvA, Etablissement Français du Sang (EFS), Assistance Publique Hopitaux de Paris (AP-HP), Institut Mondor de Recherche Biomedicale (IMRB), Creteil, France
| | - Myriam Mansour
- Univ Paris Est Creteil, Institut National de la Santé et de la Recherche Médicale (INSERM), EnvA, Etablissement Français du Sang (EFS), Assistance Publique Hopitaux de Paris (AP-HP), Institut Mondor de Recherche Biomedicale (IMRB), Creteil, France
| | - Didier Rocancourt
- Department of Developmental and Stem Cell Biology, Institut Pasteur, Paris, France
| | - Margaret Buckingham
- Department of Developmental and Stem Cell Biology, Institut Pasteur, Paris, France
| | - Frédéric Relaix
- Univ Paris Est Creteil, Institut National de la Santé et de la Recherche Médicale (INSERM), EnvA, Etablissement Français du Sang (EFS), Assistance Publique Hopitaux de Paris (AP-HP), Institut Mondor de Recherche Biomedicale (IMRB), Creteil, France
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37
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Muscle Enriched Lamin Interacting Protein ( Mlip) Binds Chromatin and Is Required for Myoblast Differentiation. Cells 2021; 10:cells10030615. [PMID: 33802236 PMCID: PMC7998221 DOI: 10.3390/cells10030615] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/08/2021] [Accepted: 03/08/2021] [Indexed: 11/20/2022] Open
Abstract
Muscle-enriched A-type lamin-interacting protein (Mlip) is a recently discovered Amniota gene that encodes proteins of unknown biological function. Here we report Mlip’s direct interaction with chromatin, and it may function as a transcriptional co-factor. Chromatin immunoprecipitations with microarray analysis demonstrated a propensity for Mlip to associate with genomic regions in close proximity to genes that control tissue-specific differentiation. Gel mobility shift assays confirmed that Mlip protein complexes with genomic DNA. Blocking Mlip expression in C2C12 myoblasts down-regulates myogenic regulatory factors (MyoD and MyoG) and subsequently significantly inhibits myogenic differentiation and the formation of myotubes. Collectively our data demonstrate that Mlip is required for C2C12 myoblast differentiation into myotubes. Mlip may exert this role as a transcriptional regulator of a myogenic program that is unique to amniotes.
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38
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Viaut C, Weldon S, Münsterberg A. Fine-tuning of the PAX-SIX-EYA-DACH network by multiple microRNAs controls embryo myogenesis. Dev Biol 2021; 469:68-79. [PMID: 33080252 DOI: 10.1016/j.ydbio.2020.10.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 10/06/2020] [Accepted: 10/14/2020] [Indexed: 01/27/2023]
Abstract
MicroRNAs (miRNAs), short non-coding RNAs, which act post-transcriptionally to regulate gene expression, are of widespread significance during development and disease, including muscle disease. Advances in sequencing technology and bioinformatics led to the identification of a large number of miRNAs in vertebrates and other species, however, for many of these miRNAs specific roles have not yet been determined. LNA in situ hybridisation has revealed expression patterns of somite-enriched miRNAs, here we focus on characterising the functions of miR-128. We show that antagomiR-mediated knockdown (KD) of miR-128 in developing chick somites has a negative impact on skeletal myogenesis. Computational analysis identified the transcription factor EYA4 as a candidate target consistent with the observation that miR-128 and EYA4 display similar expression profiles. Luciferase assays confirmed that miR-128 interacts with the EYA4 3'UTR. In vivo experiments also suggest that EYA4 is regulated by miR-128. EYA4 is a member of the PAX-SIX-EYA-DACH (PSED) network of transcription factors. Therefore, we identified additional candidate miRNA binding sites in the 3'UTR of SIX1/4, EYA1/2/3 and DACH1. Using the miRanda algorithm, we found sites for miR-128, as well as for other myogenic miRNAs, miR-1a, miR-206 and miR-133a, some of these were experimentally confirmed as functional miRNA target sites. Our results reveal that miR-128 is involved in regulating skeletal myogenesis by directly targeting EYA4 with indirect effects on other PSED members, including SIX4 and PAX3. Hence, the inhibitory effect on myogenesis observed after miR-128 knockdown was rescued by concomitant knockdown of PAX3. Moreover, we show that the PSED network of transcription factors is co-regulated by multiple muscle-enriched microRNAs.
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Affiliation(s)
- Camille Viaut
- School of Biological Sciences, Cell and Developmental Biology, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
| | - Shannon Weldon
- School of Biological Sciences, Cell and Developmental Biology, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
| | - Andrea Münsterberg
- School of Biological Sciences, Cell and Developmental Biology, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
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Bogenschutz EL, Fox ZD, Farrell A, Wynn J, Moore B, Yu L, Aspelund G, Marth G, Yandell M, Shen Y, Chung WK, Kardon G. Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias. HGG ADVANCES 2020; 1:100008. [PMID: 33263113 PMCID: PMC7703690 DOI: 10.1016/j.xhgg.2020.100008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 08/07/2020] [Indexed: 12/17/2022] Open
Abstract
The diaphragm is critical for respiration and separation of the thoracic and abdominal cavities, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The genetic etiology of CDH is complex. Single-nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs) in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple individuals and mutated genes are incompletely penetrant. This suggests that multiple genetic variants in combination, other not-yet-investigated classes of variants, and/or nongenetic factors contribute to CDH etiology. However, no studies have comprehensively investigated in affected individuals the contribution of all possible classes of variants throughout the genome to CDH etiology. In our study, we used a unique cohort of four individuals with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood and deep whole-genome sequencing to assess germline and somatic de novo and inherited SNVs, indels, and SVs. In each individual we found a different mutational landscape that included germline de novo and inherited SNVs and indels in multiple genes. We also found in two individuals a 343 bp deletion interrupting an annotated enhancer of the CDH-associated gene GATA4, and we hypothesize that this common SV (found in 1%-2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial.
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Affiliation(s)
- Eric L. Bogenschutz
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Zac D. Fox
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Andrew Farrell
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
- USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Julia Wynn
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Barry Moore
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
- USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Lan Yu
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Gudrun Aspelund
- Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Gabor Marth
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
- USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Mark Yandell
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
- USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Yufeng Shen
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA
- JP Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Wendy K. Chung
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Gabrielle Kardon
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
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40
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Boylan M, Anderson MJ, Ornitz DM, Lewandoski M. The Fgf8 subfamily (Fgf8, Fgf17 and Fgf18) is required for closure of the embryonic ventral body wall. Development 2020; 147:dev189506. [PMID: 32907848 PMCID: PMC7595690 DOI: 10.1242/dev.189506] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 08/28/2020] [Indexed: 12/26/2022]
Abstract
The closure of the embryonic ventral body wall in amniotes is an important morphogenetic event and is essential for life. Defects in human ventral wall closure are a major class of birth defect and a significant health burden. Despite this, very little is understood about how the ventral body wall is formed. Here, we show that fibroblast growth factor (FGF) ligands FGF8, FGF17 and FGF18 are essential for this process. Conditional mouse mutants for these genes display subtle migratory defects in the abdominal muscles of the ventral body wall and an enlarged umbilical ring, through which the internal organs are extruded. By refining where and when these genes are required using different Cre lines, we show that Fgf8 and Fgf17 are required in the presomitic mesoderm, whereas Fgf18 is required in the somites. This study identifies complex and multifactorial origins of ventral wall defects and has important implications for understanding their origins during embryonic development.
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Affiliation(s)
- Michael Boylan
- Cancer and Developmental Biology Lab, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
| | - Matthew J Anderson
- Cancer and Developmental Biology Lab, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
| | - David M Ornitz
- Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Mark Lewandoski
- Cancer and Developmental Biology Lab, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
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Wurmser M, Chaverot N, Madani R, Sakai H, Negroni E, Demignon J, Saint-Pierre B, Mouly V, Amthor H, Tapscott S, Birchmeier C, Tajbakhsh S, Le Grand F, Sotiropoulos A, Maire P. SIX1 and SIX4 homeoproteins regulate PAX7+ progenitor cell properties during fetal epaxial myogenesis. Development 2020; 147:dev.185975. [PMID: 32591430 DOI: 10.1242/dev.185975] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 06/18/2020] [Indexed: 01/09/2023]
Abstract
Pax7 expression marks stem cells in developing skeletal muscles and adult satellite cells during homeostasis and muscle regeneration. The genetic determinants that control the entrance into the myogenic program and the appearance of PAX7+ cells during embryogenesis are poorly understood. SIX homeoproteins are encoded by the sine oculis-related homeobox Six1-Six6 genes in vertebrates. Six1, Six2, Six4 and Six5 are expressed in the muscle lineage. Here, we tested the hypothesis that Six1 and Six4 could participate in the genesis of myogenic stem cells. We show that fewer PAX7+ cells occupy a satellite cell position between the myofiber and its associated basal lamina in Six1 and Six4 knockout mice (s1s4KO) at E18. However, PAX7+ cells are detected in remaining muscle masses present in the epaxial region of the double mutant embryos and are able to divide and contribute to muscle growth. To further characterize the properties of s1s4KO PAX7+ cells, we analyzed their transcriptome and tested their properties after transplantation in adult regenerating tibialis anterior muscle. Mutant stem cells contribute to hypotrophic myofibers that are not innervated but retain the ability to self-renew.
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Affiliation(s)
- Maud Wurmser
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Nathalie Chaverot
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Rouba Madani
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Hiroshi Sakai
- Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Toon, Ehime, 791-0295, Japan.,Stem Cells and Development, Department of Developmental and Stem Cell Biology, Institut Pasteur, 25 rue du Dr. Roux, 75015, Paris, France.,CNRS UMR 3738, Institut Pasteur, 75015 Paris, France
| | - Elisa Negroni
- Sorbonne Université, Institut de Myologie, INSERM, 75013 Paris, France
| | - Josiane Demignon
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Benjamin Saint-Pierre
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Vincent Mouly
- Sorbonne Université, Institut de Myologie, INSERM, 75013 Paris, France
| | - Helge Amthor
- INSERM U1179, LIA BAHN CSM, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France
| | | | | | - Shahragim Tajbakhsh
- Stem Cells and Development, Department of Developmental and Stem Cell Biology, Institut Pasteur, 25 rue du Dr. Roux, 75015, Paris, France.,CNRS UMR 3738, Institut Pasteur, 75015 Paris, France
| | - Fabien Le Grand
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France.,Institut NeuroMyoGène, Université Claude Bernard Lyon 1, CNRS, INSERM, 69008 Lyon, France
| | - Athanassia Sotiropoulos
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Pascal Maire
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
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Scaal M. Development of the amniote ventrolateral body wall. Dev Dyn 2020; 250:39-59. [PMID: 32406962 DOI: 10.1002/dvdy.193] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/30/2020] [Accepted: 04/30/2020] [Indexed: 12/16/2022] Open
Abstract
In vertebrates, the trunk consists of the musculoskeletal structures of the back and the ventrolateral body wall, which together enclose the internal organs of the circulatory, digestive, respiratory and urogenital systems. This review gives an overview on the development of the thoracic and abdominal wall during amniote embryogenesis. Specifically, I briefly summarize relevant historical concepts and the present knowledge on the early embryonic development of ribs, sternum, intercostal muscles and abdominal muscles with respect to anatomical bauplan, origin and specification of precursor cells, initial steps of pattern formation, and cellular and molecular regulation of morphogenesis.
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Affiliation(s)
- Martin Scaal
- Faculty of Medicine, Institute of Anatomy II, University of Cologne, Cologne, Germany
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The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma. Int J Mol Sci 2020; 21:ijms21114171. [PMID: 32545285 PMCID: PMC7312987 DOI: 10.3390/ijms21114171] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/04/2020] [Accepted: 06/09/2020] [Indexed: 12/14/2022] Open
Abstract
Glaucoma is a heterogenous, chronic, progressive group of eye diseases, which results in irreversible loss of vision. There are several types of glaucoma, whereas the primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma, accounting for three-quarters of all glaucoma cases. The pathological mechanisms leading to POAG pathogenesis are multifactorial and still poorly understood, but it is commonly known that significantly elevated intraocular pressure (IOP) plays a crucial role in POAG pathogenesis. Besides, genetic predisposition and aggregation of abrogated proteins within the endoplasmic reticulum (ER) lumen and subsequent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent unfolded protein response (UPR) signaling pathway may also constitute important factors for POAG pathogenesis at the molecular level. Glaucoma is commonly known as a ‘silent thief of sight’, as it remains asymptomatic until later stages, and thus its diagnosis is frequently delayed. Thereby, detailed knowledge about the glaucoma pathophysiology is necessary to develop both biochemical and genetic tests to improve its early diagnosis as well as develop a novel, ground-breaking treatment strategy, as currently used medical therapies against glaucoma are limited and may evoke numerous adverse side-effects in patients.
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Helmbacher F, Stricker S. Tissue cross talks governing limb muscle development and regeneration. Semin Cell Dev Biol 2020; 104:14-30. [PMID: 32517852 DOI: 10.1016/j.semcdb.2020.05.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 05/07/2020] [Accepted: 05/08/2020] [Indexed: 12/14/2022]
Abstract
For decades, limb development has been a paradigm of three-dimensional patterning. Moreover, as the limb muscles and the other tissues of the limb's musculoskeletal system arise from distinct developmental sources, it has been a prime example of integrative morphogenesis and cross-tissue communication. As the limbs grow, all components of the musculoskeletal system (muscles, tendons, connective tissue, nerves) coordinate their growth and differentiation, ultimately giving rise to a functional unit capable of executing elaborate movement. While the molecular mechanisms governing global three-dimensional patterning and formation of the skeletal structures of the limbs has been a matter of intense research, patterning of the soft tissues is less understood. Here, we review the development of limb muscles with an emphasis on their interaction with other tissue types and the instructive roles these tissues play. Furthermore, we discuss the role of adult correlates of these embryonic accessory tissues in muscle regeneration.
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Affiliation(s)
| | - Sigmar Stricker
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195, Berlin, Germany.
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Takahashi M, Ikeda K, Ohmuraya M, Nakagawa Y, Sakuma T, Yamamoto T, Kawakami K. Six1 is required for signaling center formation and labial-lingual asymmetry in developing lower incisors. Dev Dyn 2020; 249:1098-1116. [PMID: 32243674 DOI: 10.1002/dvdy.174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 03/06/2020] [Accepted: 03/26/2020] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The structure of the mouse incisor is characterized by its asymmetric accumulation of enamel matrix proteins on the labial side. The asymmetric structure originates from the patterning of the epithelial incisor placode through the interaction with dental mesenchymal cells. However, the molecular basis for the asymmetric patterning of the incisor germ is largely unknown. RESULTS A homeobox transcription factor SIX1 was shown to be produced in the mandibular mesenchyme, and its localization patterns changed dynamically during lower incisor development. Six1-/- mice exhibited smaller lower incisor primordia than wild-type mice. Furthermore, Six1-/- mice showed enamel matrix production on both the lingual and labial sides and disturbed odontoblast maturation. In the earlier stages of development, the formation of signaling centers, the initiation knot and the enamel knot, which are essential for the morphogenesis of tooth germs, were impaired in Six1-/- embryos. Notably, Wnt signaling activity, which shows an anterior-posterior gradient, and the expression patterns of genes involved in incisor formation were altered in the mesenchyme in Six1-/- embryos. CONCLUSION Our results indicate that Six1 is required for signaling center formation in lower incisor germs and the labial-lingual asymmetry of the lower incisors by regulating the anterior-posterior patterning of the mandibular mesenchyme.
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Affiliation(s)
- Masanori Takahashi
- Division of Biology, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Keiko Ikeda
- Department of Physiology, International University of Health and Welfare, Narita, Chiba, Japan
| | - Masaki Ohmuraya
- Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yoshiko Nakagawa
- Center for Animal Resources and Development, Kumamoto University, Kumamoto, Kumamoto, Japan
| | - Tetsushi Sakuma
- Division of Integrated Sciences for Life, Graduate School of Integrated Sciences for Life, Hiroshima University, HigashiHiroshima, Hiroshima, Japan
| | - Takashi Yamamoto
- Division of Integrated Sciences for Life, Graduate School of Integrated Sciences for Life, Hiroshima University, HigashiHiroshima, Hiroshima, Japan
| | - Kiyoshi Kawakami
- Division of Biology, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
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Maire P, Dos Santos M, Madani R, Sakakibara I, Viaut C, Wurmser M. Myogenesis control by SIX transcriptional complexes. Semin Cell Dev Biol 2020; 104:51-64. [PMID: 32247726 DOI: 10.1016/j.semcdb.2020.03.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 02/07/2023]
Abstract
SIX homeoproteins were first described in Drosophila, where they participate in the Pax-Six-Eya-Dach (PSED) network with eyeless, eyes absent and dachsund to drive synergistically eye development through genetic and biochemical interactions. The role of the PSED network and SIX proteins in muscle formation in vertebrates was subsequently identified. Evolutionary conserved interactions with EYA and DACH proteins underlie the activity of SIX transcriptional complexes (STC) both during embryogenesis and in adult myofibers. Six genes are expressed throughout muscle development, in embryonic and adult proliferating myogenic stem cells and in fetal and adult post-mitotic myofibers, where SIX proteins regulate the expression of various categories of genes. In vivo, SIX proteins control many steps of muscle development, acting through feedforward mechanisms: in the embryo for myogenic fate acquisition through the direct control of Myogenic Regulatory Factors; in adult myofibers for their contraction/relaxation and fatigability properties through the control of genes involved in metabolism, sarcomeric organization and calcium homeostasis. Furthermore, during development and in the adult, SIX homeoproteins participate in the genesis and the maintenance of myofibers diversity.
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Affiliation(s)
- Pascal Maire
- Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France.
| | | | - Rouba Madani
- Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France
| | - Iori Sakakibara
- Research Center for Advanced Science and Technology, The University of Tokyo, Japan
| | - Camille Viaut
- Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France
| | - Maud Wurmser
- Department of Integrative Medical Biology (IMB), Umeå universitet, Sweden
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Libetti D, Bernardini A, Sertic S, Messina G, Dolfini D, Mantovani R. The Switch from NF-YAl to NF-YAs Isoform Impairs Myotubes Formation. Cells 2020; 9:cells9030789. [PMID: 32214056 PMCID: PMC7140862 DOI: 10.3390/cells9030789] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/19/2020] [Accepted: 03/21/2020] [Indexed: 12/19/2022] Open
Abstract
NF-YA, the regulatory subunit of the trimeric transcription factor (TF) NF-Y, is regulated by alternative splicing (AS) generating two major isoforms, “long” (NF-YAl) and “short” (NF-YAs). Muscle cells express NF-YAl. We ablated exon 3 in mouse C2C12 cells by a four-guide CRISPR/Cas9n strategy, obtaining clones expressing exclusively NF-YAs (C2-YAl-KO). C2-YAl-KO cells grow normally, but are unable to differentiate. Myogenin and—to a lesser extent, MyoD— levels are substantially lower in C2-YAl-KO, before and after differentiation. Expression of the fusogenic Myomaker and Myomixer genes, crucial for the early phases of the process, is not induced. Myomaker and Myomixer promoters are bound by MyoD and Myogenin, and Myogenin overexpression induces their expression in C2-YAl-KO. NF-Y inactivation reduces MyoD and Myogenin, but not directly: the Myogenin promoter is CCAAT-less, and the canonical CCAAT of the MyoD promoter is not bound by NF-Y in vivo. We propose that NF-YAl, but not NF-YAs, maintains muscle commitment by indirectly regulating Myogenin and MyoD expression in C2C12 cells. These experiments are the first genetic evidence that the two NF-YA isoforms have functionally distinct roles.
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Cai Q, Wu G, Zhu M, Ge H, Xue C, Zhang Q, Cheng B, Xu S, Wu P. FGF6 enhances muscle regeneration after nerve injury by relying on ERK1/2 mechanism. Life Sci 2020; 248:117465. [PMID: 32105707 DOI: 10.1016/j.lfs.2020.117465] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 02/16/2020] [Accepted: 02/21/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND Severe peripheral nerve injury leads to skeletal muscle atrophy and impaired limb function that is not sufficiently improved by existing treatments. Fibroblast growth factor 6 (FGF6) is involved in tissue regeneration and is dysregulated in denervated rat muscles. However, the way that FGF6 affects skeletal muscle repair after peripheral nerve injury has not been fully elucidated. METHODS In this study, we investigated the role of FGF6 in the regeneration of denervated muscles using myoblast cells and an in vivo model of peripheral nerve injury. RESULTS FGF6 promoted the viability and migration of C2C12 and primary myoblasts in a dose-dependent manner through FGFR1-mediated upregulation of cyclin D1. Low concentrations of FGF6 promoted myoblast differentiation through FGFR4-mediated activation of ERK1/2, which upregulated expression of MyHC, MyoD, and myogenin. FGFR-1, FGFR4, MyoD, and myogenin were not upregulated when FGF6 expression was inhibited in myoblasts by shRNA-mediated knockdown. Injection of FGF6 into denervated rat muscles enhanced the MyHC-IIb muscle fiber phenotype and prevented muscular atrophy. CONCLUSION These findings indicate that FGF6 reduces skeletal muscle atrophy by relying on the ERK1/2 mechanism and enhances the conversion of slow muscle to fast muscle fibers, thereby promoting functional recovery of regenerated skeletal muscle after innervation.
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Affiliation(s)
- Qiuchen Cai
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China
| | - Genbin Wu
- Department of Joint Surgery, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai 200120, China
| | - Min Zhu
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China
| | - Heng''an Ge
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China
| | - Chao Xue
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China
| | - Qing''gang Zhang
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China
| | - Biao Cheng
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China
| | - Sudan Xu
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
| | - Peng Wu
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China.
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Mukund K, Subramaniam S. Skeletal muscle: A review of molecular structure and function, in health and disease. WILEY INTERDISCIPLINARY REVIEWS. SYSTEMS BIOLOGY AND MEDICINE 2020; 12:e1462. [PMID: 31407867 PMCID: PMC6916202 DOI: 10.1002/wsbm.1462] [Citation(s) in RCA: 279] [Impact Index Per Article: 55.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 07/03/2019] [Accepted: 07/03/2019] [Indexed: 12/11/2022]
Abstract
Decades of research in skeletal muscle physiology have provided multiscale insights into the structural and functional complexity of this important anatomical tissue, designed to accomplish the task of generating contraction, force and movement. Skeletal muscle can be viewed as a biomechanical device with various interacting components including the autonomic nerves for impulse transmission, vasculature for efficient oxygenation, and embedded regulatory and metabolic machinery for maintaining cellular homeostasis. The "omics" revolution has propelled a new era in muscle research, allowing us to discern minute details of molecular cross-talk required for effective coordination between the myriad interacting components for efficient muscle function. The objective of this review is to provide a systems-level, comprehensive mapping the molecular mechanisms underlying skeletal muscle structure and function, in health and disease. We begin this review with a focus on molecular mechanisms underlying muscle tissue development (myogenesis), with an emphasis on satellite cells and muscle regeneration. We next review the molecular structure and mechanisms underlying the many structural components of the muscle: neuromuscular junction, sarcomere, cytoskeleton, extracellular matrix, and vasculature surrounding muscle. We highlight aberrant molecular mechanisms and their possible clinical or pathophysiological relevance. We particularly emphasize the impact of environmental stressors (inflammation and oxidative stress) in contributing to muscle pathophysiology including atrophy, hypertrophy, and fibrosis. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Developmental Biology > Developmental Processes in Health and Disease Models of Systems Properties and Processes > Cellular Models.
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Affiliation(s)
- Kavitha Mukund
- Department of BioengineeringUniversity of CaliforniaSan DiegoCalifornia
| | - Shankar Subramaniam
- Department of Bioengineering, Bioinformatics & Systems BiologyUniversity of CaliforniaSan DiegoCalifornia
- Department of Computer Science and EngineeringUniversity of CaliforniaSan DiegoCalifornia
- Department of Cellular and Molecular Medicine and NanoengineeringUniversity of CaliforniaSan DiegoCalifornia
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Efficient genome-wide first-generation phenotypic screening system in mice using the piggyBac transposon. Proc Natl Acad Sci U S A 2019; 116:18507-18516. [PMID: 31451639 DOI: 10.1073/pnas.1906354116] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Genome-wide phenotypic screens provide an unbiased way to identify genes involved in particular biological traits, and have been widely used in lower model organisms. However, cost and time have limited the utility of such screens to address biological and disease questions in mammals. Here we report a highly efficient piggyBac (PB) transposon-based first-generation (F1) dominant screening system in mice that enables an individual investigator to conduct a genome-wide phenotypic screen within a year with fewer than 300 cages. The PB screening system uses visually trackable transposons to induce both gain- and loss-of-function mutations and generates genome-wide distributed new insertions in more than 55% of F1 progeny. Using this system, we successfully conducted a pilot F1 screen and identified 5 growth retardation mutations. One of these mutants, a Six1/4 PB/+ mutant, revealed a role in milk intake behavior. The mutant animals exhibit abnormalities in nipple recognition and milk ingestion, as well as developmental defects in cranial nerves V, IX, and X. This PB F1 screening system offers individual laboratories unprecedented opportunities to conduct affordable genome-wide phenotypic screens for deciphering the genetic basis of mammalian biology and disease pathogenesis.
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