|
1
|
Fonseca PAS, Suárez-Vega A, Arranz JJ, Gutiérrez-Gil B. Integration of selective sweeps across the sheep genome: understanding the relationship between production and adaptation traits. Genet Sel Evol 2024; 56:40. [PMID: 38773423 PMCID: PMC11106937 DOI: 10.1186/s12711-024-00910-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 05/07/2024] [Indexed: 05/23/2024] Open
Abstract
BACKGROUND Livestock populations are under constant selective pressure for higher productivity levels for different selective purposes. This pressure results in the selection of animals with unique adaptive and production traits. The study of genomic regions associated with these unique characteristics has the potential to improve biological knowledge regarding the adaptive process and how it is connected to production levels and resilience, which is the ability of an animal to adapt to stress or an imbalance in homeostasis. Sheep is a species that has been subjected to several natural and artificial selective pressures during its history, resulting in a highly specialized species for production and adaptation to challenging environments. Here, the data from multiple studies that aim at mapping selective sweeps across the sheep genome associated with production and adaptation traits were integrated to identify confirmed selective sweeps (CSS). RESULTS In total, 37 studies were used to identify 518 CSS across the sheep genome, which were classified as production (147 prodCSS) and adaptation (219 adapCSS) CSS based on the frequency of each type of associated study. The genes within the CSS were associated with relevant biological processes for adaptation and production. For example, for adapCSS, the associated genes were related to the control of seasonality, circadian rhythm, and thermoregulation. On the other hand, genes associated with prodCSS were related to the control of feeding behaviour, reproduction, and cellular differentiation. In addition, genes harbouring both prodCSS and adapCSS showed an interesting association with lipid metabolism, suggesting a potential role of this process in the regulation of pleiotropic effects between these classes of traits. CONCLUSIONS The findings of this study contribute to a deeper understanding of the genetic link between productivity and adaptability in sheep breeds. This information may provide insights into the genetic mechanisms that underlie undesirable genetic correlations between these two groups of traits and pave the way for a better understanding of resilience as a positive ability to respond to environmental stressors, where the negative effects on production level are minimized.
Collapse
Affiliation(s)
- Pablo A S Fonseca
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana S/N, 24071, León, Spain
| | - Aroa Suárez-Vega
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana S/N, 24071, León, Spain
| | - Juan J Arranz
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana S/N, 24071, León, Spain
| | - Beatriz Gutiérrez-Gil
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana S/N, 24071, León, Spain.
| |
Collapse
|
|
2
|
Xing YZ, Guo HY, Xiang F, Li YH. Recent progress in hair follicle stem cell markers and their regulatory roles. World J Stem Cells 2024; 16:126-136. [PMID: 38455104 PMCID: PMC10915958 DOI: 10.4252/wjsc.v16.i2.126] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/19/2023] [Accepted: 01/16/2024] [Indexed: 02/26/2024] Open
Abstract
Hair follicle stem cells (HFSCs) in the bulge are a multipotent adult stem cell population. They can periodically give rise to new HFs and even regenerate the epidermis and sebaceous glands during wound healing. An increasing number of biomarkers have been used to isolate, label, and trace HFSCs in recent years. Considering more detailed data from single-cell transcriptomics technology, we mainly focus on the important HFSC molecular markers and their regulatory roles in this review.
Collapse
Affiliation(s)
- Yi-Zhan Xing
- Department of Cell Biology, Army Medical University, Chongqing 400038, China
| | - Hai-Ying Guo
- Department of Cell Biology, Army Medical University, Chongqing 400038, China
| | - Fei Xiang
- Institute of Burn Research, Southwest Hospital, Army Medical University, Chongqing 400038, China
| | - Yu-Hong Li
- Department of Cell Biology, Army Medical University, Chongqing 400038, China.
| |
Collapse
|
|
3
|
Lv X, He M, Zhou H, Wang S, Cao X, Yuan Z, Getachew T, Li Y, Sun W. SP1 and KROX20 Regulate the Proliferation of Dermal Papilla Cells and Target the CUX1 Gene. Animals (Basel) 2024; 14:429. [PMID: 38338072 PMCID: PMC10854491 DOI: 10.3390/ani14030429] [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: 01/04/2024] [Revised: 01/23/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Previous studies have demonstrated that CUX1 could contribute to the proliferation of DPCs in vitro, but the upstream transcriptional regulatory mechanisms of CUX1 remain largely unknown. This study aimed to investigate the upstream transcriptional regulators of CUX1 to enhance our comprehension of the mechanism of action of the CUX1 gene in ovine DPCs. Initially, the JASPAR (2024) software was used to predict the upstream target transcription factors for the CUX1 gene. Subsequently, through RT-qPCR and a double luciferase reporter assay, the interaction between SP1, KROX20, and CUX1 was established, respectively. The results indicated that SP1 and KROX20 were two highly reliable upstream transcription regulators for the CUX1 gene. Additionally, we found that SP1 promoted the proliferation of DPCs by overexpressing SP1 in DPCs, and KROX20 inhibited the proliferation of DPCs by overexpressing KROX20 in DPCs. These findings are also consistent with the transcriptional regulation of CUX1 by SP1 and KROX20, respectively. This study suggests that the effect of DPC proliferation in vitro by CUX1 may regulated by the transcription factors SP1 and KROX20.
Collapse
Affiliation(s)
- Xiaoyang Lv
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China; (X.L.); (Z.Y.)
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
| | - Mingliang He
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Hui Zhou
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Shanhe Wang
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xiukai Cao
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China; (X.L.); (Z.Y.)
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
| | - Zehu Yuan
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China; (X.L.); (Z.Y.)
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
| | - Tesfaye Getachew
- International Centre for Agricultural Research in the Dry Areas, Addis Ababa 999047, Ethiopia
| | - Yutao Li
- CSIRO Agriculture and Food, 306 Carmody Rd, St Lucia, QLD 4067, Australia
| | - Wei Sun
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China; (X.L.); (Z.Y.)
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| |
Collapse
|
|
4
|
Rozen EJ, Ozeroff CD, Allen MA. RUN(X) out of blood: emerging RUNX1 functions beyond hematopoiesis and links to Down syndrome. Hum Genomics 2023; 17:83. [PMID: 37670378 PMCID: PMC10481493 DOI: 10.1186/s40246-023-00531-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 08/29/2023] [Indexed: 09/07/2023] Open
Abstract
BACKGROUND RUNX1 is a transcription factor and a master regulator for the specification of the hematopoietic lineage during embryogenesis and postnatal megakaryopoiesis. Mutations and rearrangements on RUNX1 are key drivers of hematological malignancies. In humans, this gene is localized to the 'Down syndrome critical region' of chromosome 21, triplication of which is necessary and sufficient for most phenotypes that characterize Trisomy 21. MAIN BODY Individuals with Down syndrome show a higher predisposition to leukemias. Hence, RUNX1 overexpression was initially proposed as a critical player on Down syndrome-associated leukemogenesis. Less is known about the functions of RUNX1 in other tissues and organs, although growing reports show important implications in development or homeostasis of neural tissues, muscle, heart, bone, ovary, or the endothelium, among others. Even less is understood about the consequences on these tissues of RUNX1 gene dosage alterations in the context of Down syndrome. In this review, we summarize the current knowledge on RUNX1 activities outside blood/leukemia, while suggesting for the first time their potential relation to specific Trisomy 21 co-occurring conditions. CONCLUSION Our concise review on the emerging RUNX1 roles in different tissues outside the hematopoietic context provides a number of well-funded hypotheses that will open new research avenues toward a better understanding of RUNX1-mediated transcription in health and disease, contributing to novel potential diagnostic and therapeutic strategies for Down syndrome-associated conditions.
Collapse
Affiliation(s)
- Esteban J Rozen
- Crnic Institute Boulder Branch, BioFrontiers Institute, University of Colorado Boulder, 3415 Colorado Ave., Boulder, CO, 80303, USA.
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO, 80045, USA.
| | - Christopher D Ozeroff
- Crnic Institute Boulder Branch, BioFrontiers Institute, University of Colorado Boulder, 3415 Colorado Ave., Boulder, CO, 80303, USA
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO, 80045, USA
- Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, 1945 Colorado Ave., Boulder, CO, 80309, USA
| | - Mary Ann Allen
- Crnic Institute Boulder Branch, BioFrontiers Institute, University of Colorado Boulder, 3415 Colorado Ave., Boulder, CO, 80303, USA.
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO, 80045, USA.
| |
Collapse
|
|
5
|
Sunkara RR, Mehta D, Sarate RM, Waghmare SK. BMP-AKT-GSK3β signalling restores hair follicle stem cells decrease associated with loss of Sfrp1. Stem Cells 2022; 40:802-817. [PMID: 35689817 DOI: 10.1093/stmcls/sxac041] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 04/05/2022] [Indexed: 11/15/2022]
Abstract
Wnt signaling plays a pivotal role in regulating activation, proliferation, stem cell renewal and differentiation of hair follicle stem cells (HFSCs). Secreted frizzled related protein-1 (Sfrp1), a Wnt antagonist is up regulated in the HFSCs; however, its role in the HFSCs regulation is still obscure. Here, we show that Sfrp1 loss showed a depletion of HFSCs, enhanced HFSC proliferation and faster hair follicle cycle at PD21 to PD28, HFSC markers such as Lgr5 and Axin2 were decreased in both the Sfrp1 +/- and Sfrp1 -/- HFSCs. In addition, the second hair follicle cycle was also faster as compared to WT. Importantly, Sfrp1 -/- showed a restoration of HFSC by 2 nd telogen (PD49), while Sfrp1+/- did not show restoration with still having a decreased HFSC. Infact, restoration of HFSCs was due to a pronounced down-regulation of β-CATENIN activity mediated through a cross-talk of BMP-AKT-GSK3β signalling in Sfrp1-/- as compared to Sfrp1+/-, where down regulation was less pronounced. In cultured keratinocytes, Sfrp1 loss resulted in enhanced proliferation and clonogenicity, which were reversed by treating with either BMPR1A or GSK3β inhibitor thereby confirming BMP-AKT-GSK3β signaling involved in β-CATENIN regulation in both the Sfrp1 +/- and Sfrp1 -/- mice. Our study reveals a novel function of Sfrp1 by unravelling an in vivo molecular mechanism that regulate the HFSCs pool mediated through a hitherto unknown cross-talk of BMP-AKT-GSK3β signalling that maintain stem cell pool balance, which in turn maintain skin tissue homeostasis.
Collapse
Affiliation(s)
- Raghava R Sunkara
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Darshan Mehta
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Rahul M Sarate
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Sanjeev K Waghmare
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| |
Collapse
|
|
6
|
Tran A, Yang P, Yang JYH, Ormerod JT. scREMOTE: Using multimodal single cell data to predict regulatory gene relationships and to build a computational cell reprogramming model. NAR Genom Bioinform 2022; 4:lqac023. [PMID: 35300460 PMCID: PMC8923006 DOI: 10.1093/nargab/lqac023] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 02/22/2022] [Accepted: 03/10/2022] [Indexed: 11/12/2022] Open
Abstract
Cell reprogramming offers a potential treatment to many diseases, by regenerating specialized somatic cells. Despite decades of research, discovering the transcription factors that promote cell reprogramming has largely been accomplished through trial and error, a time-consuming and costly method. A computational model for cell reprogramming, however, could guide the hypothesis formulation and experimental validation, to efficiently utilize time and resources. Current methods often cannot account for the heterogeneity observed in cell reprogramming, or they only make short-term predictions, without modelling the entire reprogramming process. Here, we present scREMOTE, a novel computational model for cell reprogramming that leverages single cell multiomics data, enabling a more holistic view of the regulatory mechanisms at cellular resolution. This is achieved by first identifying the regulatory potential of each transcription factor and gene to uncover regulatory relationships, then a regression model is built to estimate the effect of transcription factor perturbations. We show that scREMOTE successfully predicts the long-term effect of overexpressing two key transcription factors in hair follicle development by capturing higher-order gene regulations. Together, this demonstrates that integrating the multimodal processes governing gene regulation creates a more accurate model for cell reprogramming with significant potential to accelerate research in regenerative medicine.
Collapse
Affiliation(s)
- Andy Tran
- School of Mathematics and Statistics, The University of Sydney, Camperdown NSW 2006, Australia
| | - Pengyi Yang
- School of Mathematics and Statistics, The University of Sydney, Camperdown NSW 2006, Australia
| | - Jean Y H Yang
- School of Mathematics and Statistics, The University of Sydney, Camperdown NSW 2006, Australia
| | - John T Ormerod
- School of Mathematics and Statistics, The University of Sydney, Camperdown NSW 2006, Australia
| |
Collapse
|
|
7
|
Mevel R, Draper JE, Lie-A-Ling M, Kouskoff V, Lacaud G. RUNX transcription factors: orchestrators of development. Development 2019; 146:dev148296. [PMID: 31488508 DOI: 10.1242/dev.148296] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
RUNX transcription factors orchestrate many different aspects of biology, including basic cellular and developmental processes, stem cell biology and tumorigenesis. In this Primer, we introduce the molecular hallmarks of the three mammalian RUNX genes, RUNX1, RUNX2 and RUNX3, and discuss the regulation of their activities and their mechanisms of action. We then review their crucial roles in the specification and maintenance of a wide array of tissues during embryonic development and adult homeostasis.
Collapse
Affiliation(s)
- Renaud Mevel
- Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Alderley Edge, Macclesfield SK10 4TG, UK
| | - Julia E Draper
- Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Alderley Edge, Macclesfield SK10 4TG, UK
| | - Michael Lie-A-Ling
- Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Alderley Edge, Macclesfield SK10 4TG, UK
| | - Valerie Kouskoff
- Division of Developmental Biology & Medicine, The University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK
| | - Georges Lacaud
- Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Alderley Edge, Macclesfield SK10 4TG, UK
| |
Collapse
|
|
8
|
Hong D, Fritz AJ, Gordon JA, Tye CE, Boyd JR, Tracy KM, Frietze SE, Carr FE, Nickerson JA, Van Wijnen AJ, Imbalzano AN, Zaidi SK, Lian JB, Stein JL, Stein GS. RUNX1-dependent mechanisms in biological control and dysregulation in cancer. J Cell Physiol 2019; 234:8597-8609. [PMID: 30515788 PMCID: PMC6395522 DOI: 10.1002/jcp.27841] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 11/12/2018] [Indexed: 01/02/2023]
Abstract
The RUNX1 transcription factor has recently been shown to be obligatory for normal development. RUNX1 controls the expression of genes essential for proper development in many cell lineages and tissues including blood, bone, cartilage, hair follicles, and mammary glands. Compromised RUNX1 regulation is associated with many cancers. In this review, we highlight evidence for RUNX1 control in both invertebrate and mammalian development and recent novel findings of perturbed RUNX1 control in breast cancer that has implications for other solid tumors. As RUNX1 is essential for definitive hematopoiesis, RUNX1 mutations in hematopoietic lineage cells have been implicated in the etiology of several leukemias. Studies of solid tumors have revealed a context-dependent function for RUNX1 either as an oncogene or a tumor suppressor. These RUNX1 functions have been reported for breast, prostate, lung, and skin cancers that are related to cancer subtypes and different stages of tumor development. Growing evidence suggests that RUNX1 suppresses aggressiveness in most breast cancer subtypes particularly in the early stage of tumorigenesis. Several studies have identified RUNX1 suppression of the breast cancer epithelial-to-mesenchymal transition. Most recently, RUNX1 repression of cancer stem cells and tumorsphere formation was reported for breast cancer. It is anticipated that these new discoveries of the context-dependent diversity of RUNX1 functions will lead to innovative therapeutic strategies for the intervention of cancer and other abnormalities of normal tissues.
Collapse
Affiliation(s)
- Deli Hong
- Dana Farber Cancer Institute, Boston, Massachusetts
| | - Andrew J Fritz
- Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, Vermont
| | - Jonathan A Gordon
- Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, Vermont
| | - Coralee E Tye
- Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, Vermont
| | - Joseph R Boyd
- Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, Vermont
| | - Kirsten M Tracy
- Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, Vermont
| | - Seth E Frietze
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, Vermont
| | - Frances E. Carr
- Department of Pharmacology, University of Vermont, Burlington, Vermont
| | | | - Andre J. Van Wijnen
- Departments of Orthopedic Surgery and Biochemistry & Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Anthony N. Imbalzano
- Graduate Program in Cell Biology and Department of Biochemistry and Molecular Pharmacology, UMass Medical School, Worcester, Massachusetts
| | - Sayyed K. Zaidi
- Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, Vermont
| | - Jane B. Lian
- Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, Vermont
| | - Janet L. Stein
- Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, Vermont
| | - Gary S. Stein
- Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, Vermont
| |
Collapse
|
|
9
|
Runx1-Stat3 signaling regulates the epithelial stem cells in continuously growing incisors. Sci Rep 2018; 8:10906. [PMID: 30026553 PMCID: PMC6053438 DOI: 10.1038/s41598-018-29317-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 07/09/2018] [Indexed: 11/08/2022] Open
Abstract
Rodent incisors grow permanently and the homeostasis of enamel production is maintained by a continuous supply of epithelial progenitors from putative stem cells in the cervical loop. We herein report that Runx1 regulates the Lgr5-expressing epithelial stem cells and their subsequent continuous differentiation into ameloblasts. Mice deficient in epithelial Runx1 demonstrate remarkable shortening of the incisors with underdevelopment of the cervical loop and enamel defects. In this mutant cervical loop, the proliferation of the dental epithelium was significantly disturbed and the expression of Lgr5 and enamel matrix proteins was remarkably downregulated. Interestingly, the expression of Socs3, an inhibitor of Stat3 signaling, was upregulated and Stat3 phosphorylation was suppressed specifically in the mutant cervical loop. The expression of Lgr5 and the enamel matrix protein in the wild-type incisor germs is disturbed by pharmaceutical Stat3 inhibition in vitro., of. Conversely, pharmaceutical activation of Stat3 rescues the defective phenotypes of the Runx1 mutant with upregulated Lgr5 and enamel matrix protein genes. The present results provide the first evidence of the role of Runx1 regulates the Lgr5-expressing epithelial stem cells and differentiation of ameloblast progenitors in the developing incisors. Our study also demonstrates that Stat3 modulates the Runx1-Lgr5 axis in the cervical loop.
Collapse
|
|
10
|
Chuang LSH, Ito K, Ito Y. Roles of RUNX in Solid Tumors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 962:299-320. [PMID: 28299665 DOI: 10.1007/978-981-10-3233-2_19] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
All RUNX genes have been implicated in the development of solid tumors, but the role each RUNX gene plays in the different tumor types is complicated by multiple interactions with major signaling pathways and tumor heterogeneity. Moreover, for a given tissue type, the specific role of each RUNX protein is distinct at different stages of differentiation. A regulatory function for RUNX in tissue stem cells points sharply to a causal effect in tumorigenesis. Understanding how RUNX dysregulation in cancer impinges on normal biological processes is important for identifying the molecular mechanisms that lead to malignancy. It will also indicate whether restoration of proper RUNX function to redirect cell fate is a feasible treatment for cancer. With the recent advances in RUNX research, it is time to revisit the many mechanisms/pathways that RUNX engage to regulate cell fate and decide whether cells proliferate, differentiate or die.
Collapse
Affiliation(s)
- Linda Shyue Huey Chuang
- Cancer Science Institute of Singapore, Center for Translational Medicine, National University of Singapore, 14 Medical Drive #12-01, Singapore, 117599, Singapore
| | - Kosei Ito
- Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan
| | - Yoshiaki Ito
- Cancer Science Institute of Singapore, Center for Translational Medicine, National University of Singapore, 14 Medical Drive #12-01, Singapore, 117599, Singapore.
| |
Collapse
|
|
11
|
Ferreira MS, Alves PC, Callahan CM, Marques JP, Mills LS, Good JM, Melo‐Ferreira J. The transcriptional landscape of seasonal coat colour moult in the snowshoe hare. Mol Ecol 2017; 26:4173-4185. [DOI: 10.1111/mec.14177] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 05/03/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Mafalda S. Ferreira
- CIBIO Centro de Investigação em Biodiversidade e Recursos Genéticos InBIO Laboratório Associado Universidade do Porto Vairão Portugal
- Departamento de Biologia Faculdade de Ciências da Universidade do Porto Porto Portugal
| | - Paulo C. Alves
- CIBIO Centro de Investigação em Biodiversidade e Recursos Genéticos InBIO Laboratório Associado Universidade do Porto Vairão Portugal
- Departamento de Biologia Faculdade de Ciências da Universidade do Porto Porto Portugal
- Wildlife Biology Program University of Montana Missoula MT USA
| | - Colin M. Callahan
- Division of Biological Sciences University of Montana Missoula MT USA
| | - João P. Marques
- CIBIO Centro de Investigação em Biodiversidade e Recursos Genéticos InBIO Laboratório Associado Universidade do Porto Vairão Portugal
- Departamento de Biologia Faculdade de Ciências da Universidade do Porto Porto Portugal
| | - L. Scott Mills
- Wildlife Biology Program University of Montana Missoula MT USA
- Department of Forestry and Environmental Resources Fisheries, Wildlife and Conservation Biology Program North Carolina State University Raleigh NC USA
| | - Jeffrey M. Good
- Division of Biological Sciences University of Montana Missoula MT USA
| | - José Melo‐Ferreira
- CIBIO Centro de Investigação em Biodiversidade e Recursos Genéticos InBIO Laboratório Associado Universidade do Porto Vairão Portugal
- Departamento de Biologia Faculdade de Ciências da Universidade do Porto Porto Portugal
| |
Collapse
|
|
12
|
Runx Family Genes in Tissue Stem Cell Dynamics. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 962:117-138. [PMID: 28299655 DOI: 10.1007/978-981-10-3233-2_9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The Runx family genes play important roles in development and cancer, largely via their regulation of tissue stem cell behavior. Their involvement in two organs, blood and skin, is well documented. This review summarizes currently known Runx functions in the stem cells of these tissues. The fundamental core mechanism(s) mediated by Runx proteins has been sought; however, it appears that there does not exist one single common machinery that governs both tissue stem cells. Instead, Runx family genes employ multiple spatiotemporal mechanisms in regulating individual tissue stem cell populations. Such specific Runx requirements have been unveiled by a series of cell type-, developmental stage- or age-specific gene targeting studies in mice. Observations from these experiments revealed that the regulation of stem cells by Runx family genes turned out to be far more complex than previously thought. For instance, although it has been reported that Runx1 is required for the endothelial-to-hematopoietic cell transition (EHT) but not thereafter, recent studies clearly demonstrated that Runx1 is also needed during the period subsequent to EHT, namely at perinatal stage. In addition, Runx1 ablation in the embryonic skin mesenchyme eventually leads to complete loss of hair follicle stem cells (HFSCs) in the adult epithelium, suggesting that Runx1 facilitates the specification of skin epithelial stem cells in a cell extrinsic manner. Further in-depth investigation into how Runx family genes are involved in stem cell regulation is warranted.
Collapse
|
|
13
|
Jin M, Liu N, Yuan S, Piao J, Zhao F, Qu Y, Zhang T, Wang Y. Construction of a cDNA library and identification of genes from Liaoning cashmere goat. Livest Sci 2014. [DOI: 10.1016/j.livsci.2014.02.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
14
|
Nissimov JN, Das Chaudhuri AB. Hair curvature: a natural dialectic and review. Biol Rev Camb Philos Soc 2014; 89:723-66. [PMID: 24617997 DOI: 10.1111/brv.12081] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 12/18/2013] [Accepted: 01/01/2014] [Indexed: 12/19/2022]
Abstract
Although hair forms (straight, curly, wavy, etc.) are present in apparently infinite variations, each fibre can be reduced to a finite sequence of tandem segments of just three types: straight, bent/curly, or twisted. Hair forms can thus be regarded as resulting from genetic pathways that induce, reverse or modulate these basic curvature modes. However, physical interconversions between twists and curls demonstrate that strict one-to-one correspondences between them and their genetic causes do not exist. Current hair-curvature theories do not distinguish between bending and twisting mechanisms. We here introduce a multiple papillary centres (MPC) model which is particularly suitable to explain twisting. The model combines previously known features of hair cross-sectional morphology with partially/completely separated dermal papillae within single follicles, and requires such papillae to induce differential growth rates of hair cortical material in their immediate neighbourhoods. The MPC model can further help to explain other, poorly understood, aspects of hair growth and morphology. Separate bending and twisting mechanisms would be preferentially affected at the major or minor ellipsoidal sides of fibres, respectively, and together they exhaust the possibilities for influencing hair-form phenotypes. As such they suggest dialectic for hair-curvature development. We define a natural-dialectic (ND) which could take advantage of speculative aspects of dialectic, but would verify its input data and results by experimental methods. We use this as a top-down approach to first define routes by which hair bending or twisting may be brought about and then review evidence in support of such routes. In particular we consider the wingless (Wnt) and mammalian target of rapamycin (mTOR) pathways as paradigm pathways for molecular hair bending and twisting mechanisms, respectively. In addition to the Wnt canonical pathway, the Wnt/Ca(2+) and planar cell polarity (PCP) pathways, and others, can explain many alternatives and specific variations of hair bending phenotypes. Mechanisms for hair papilla budding or its division by bisection or fission can explain MPC formation. Epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions, acting in collaboration with epithelial-mesenchymal communications are also considered as mechanisms affecting hair growth and its bending and twisting. These may be treated as sub-mechanisms of an overall development from neural-crest stem cell (NCSC) lineages to differentiated hair follicle (HF) cell types, thus providing a unified framework for hair growth and development.
Collapse
|
|
15
|
Scheitz CJF, Tumbar T. New insights into the role of Runx1 in epithelial stem cell biology and pathology. J Cell Biochem 2013; 114:985-93. [PMID: 23150456 PMCID: PMC5788165 DOI: 10.1002/jcb.24453] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Accepted: 10/30/2012] [Indexed: 12/29/2022]
Abstract
The transcription factor Runx1 has been studied in leukemia and blood for decades, but recently it has been also implicated in epithelial biology and pathology. Particularly in mouse skin Runx1 modulates Wnt signaling levels thereby regulating timely induction of hair follicle specification, proper maturation of the emerging adult hair follicle stem cells in embryogenesis, and timely stem cell (SC) activation during adult homeostasis. Moreover, Runx1 acts as a tumor promoter in mouse skin squamous tumor formation and maintenance, likely by repressing p21 and promoting Stat3 activation. Similarly, Runx1 is essential for oral epithelium tumorigenesis mediated in mice by Ras, and for growth of three kinds of human epithelial cancer cells. In contrast, Runx1 has a tumor suppressor function in the mouse intestine and shows tumor subtype specific behavior in human breast cancer. Multiple studies revealed Runx1 SNPs to be associated with human cancers and autoimmune disease. With this information as background, the field is poised for functional and mechanistic studies to elucidate the role of Runx1 in formation and/or progression of epithelial-based human disease.
Collapse
Affiliation(s)
| | - Tudorita Tumbar
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853
| |
Collapse
|
|
16
|
|
|
17
|
Lee B, Dai X. Transcriptional control of epidermal stem cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 786:157-73. [PMID: 23696356 DOI: 10.1007/978-94-007-6621-1_9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Transcriptional regulation is fundamentally important for the progression of tissue stem cells through different stages of development and differentiation. Mammalian skin epidermis is an excellent model system to study such regulatory mechanisms due to its easy accessibility, stereotypic spatial arrangement, and availability of well-established cell type/lineage differentiation markers. Moreover, epidermis is one of the few mammalian tissues the stem cells of which can be maintained and propagated in culture to generate mature cell types and a functional tissue (reviewed in [1]), offering in vitro and ex vivo platforms to probe deep into the underlying cell and molecular mechanisms of biological functions.
Collapse
Affiliation(s)
- Briana Lee
- Department of Biological Chemistry, School of Medicine, University of California, D250 Med Sci I, Irvine 92697-1700, CA, USA
| | | |
Collapse
|
|
18
|
Okano J, Levy C, Lichti U, Sun HW, Yuspa SH, Sakai Y, Morasso MI. Cutaneous retinoic acid levels determine hair follicle development and downgrowth. J Biol Chem 2012; 287:39304-15. [PMID: 23007396 DOI: 10.1074/jbc.m112.397273] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Retinoic acid (RA) is essential during embryogenesis and for tissue homeostasis, whereas excess RA is well known as a teratogen. In humans, excess RA is associated with hair loss. In the present study, we demonstrate that specific levels of RA, regulated by Cyp26b1, one of the RA-degrading enzymes, are required for hair follicle (hf) morphogenesis. Mice with embryonic ablation of Cyp26b1 (Cyp26b1(-/-)) have excessive endogenous RA, resulting in arrest of hf growth at the hair germ stage. The altered hf development is rescued by grafting the mutant skin on immunodeficient mice. Our results show that normalization of RA levels is associated with reinitiation of hf development. Conditional deficiency of Cyp26b1 in the dermis (En1Cre;Cyp26b1f/-) results in decreased hair follicle density and specific effect on hair type, indicating that RA levels also influence regulators of hair bending. Our results support the model of RA-dependent dermal signals regulating hf downgrowth and bending. To elucidate target gene pathways of RA, we performed microarray and RNA-Seq profiling of genes differentially expressed in Cyp26b1(-/-) skin and En1Cre;Cyp26b1f/- tissues. We show specific effects on the Wnt-catenin pathway and on members of the Runx, Fox, and Sox transcription factor families, indicating that RA modulates pathways and factors implicated in hf downgrowth and bending. Our results establish that proper RA distribution is essential for morphogenesis, development, and differentiation of hfs.
Collapse
Affiliation(s)
- Junko Okano
- Developmental Skin Biology Section, NIAMS, National Institutes of Health, Bethesda, Maryland 20892, USA
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Kurosaka H, Islam MN, Kuremoto KI, Hayano S, Nakamura M, Kawanabe N, Yanagita T, Rice DPC, Harada H, Taniuchi I, Yamashiro T. Core binding factor beta functions in the maintenance of stem cells and orchestrates continuous proliferation and differentiation in mouse incisors. Stem Cells 2012; 29:1792-803. [PMID: 21898689 DOI: 10.1002/stem.722] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Rodent incisors grow continuously throughout life, and epithelial progenitor cells are supplied from stem cells in the cervical loop. We report that epithelial Runx genes are involved in the maintenance of epithelial stem cells and their subsequent continuous differentiation and therefore growth of the incisors. Core binding factor β (Cbfb) acts as a binding partner for all Runx proteins, and targeted inactivation of this molecule abrogates the activity of all Runx complexes. Mice deficient in epithelial Cbfb produce short incisors and display marked underdevelopment of the cervical loop and suppressed epithelial Fgf9 expression and mesenchymal Fgf3 and Fgf10 expression in the cervical loop. In culture, FGF9 protein rescues these phenotypes. These findings indicate that epithelial Runx functions to maintain epithelial stem cells and that Fgf9 may be a target gene of Runx signaling. Cbfb mutants also lack enamel formation and display downregulated Shh mRNA expression in cells differentiating into ameloblasts. Furthermore, Fgf9 deficiency results in a proximal shift of the Shh expressing cell population and ectopic FGF9 protein suppresses Shh expression. These findings indicate that Shh as well as Fgf9 expression is maintained by Runx/Cbfb but that Fgf9 antagonizes Shh expression. The present results provide the first genetic evidence that Runx/Cbfb genes function in the maintenance of stem cells in developing incisors by activating Fgf signaling loops between the epithelium and mesenchyme. In addition, Runx genes also orchestrate continuous proliferation and differentiation by maintaining the expression of Fgf9 and Shh mRNA.
Collapse
Affiliation(s)
- Hiroshi Kurosaka
- Department of Orthodontics, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Tumbar T. Ontogeny and Homeostasis of Adult Epithelial Skin Stem Cells. Stem Cell Rev Rep 2012; 8:10.1007/s12015-012-9348-9. [PMID: 22290419 PMCID: PMC4103971 DOI: 10.1007/s12015-012-9348-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mouse epithelial skin stem cells constitute an important model system for understanding the dynamics of stem cell emergence and behavior in an intact vertebrate tissue. Recent published work defined discrete populations of epithelial stem cells in the adult skin epithelium, which reside in the hair follicle bulge and germ, isthmus, sebaceous gland and inter-follicular epidermis. Adult epidermal and hair follicle stem cells seem to adopt mostly symmetric or unidirectional fate decisions of either one of two possible fates: (1) differentiate and be lost from the tissue or (2) expand symmetrically to self-renew. Asymmetric divisions appear to be mostly implicated in differentiation and stratification of the epidermis. While mechanisms of adult stem cell homeostasis begin to be unraveled, the embryonic origin of the adult epithelial skin stem cells is poorly understood. Recent studies reported Sox9, Lgr6, and Runx1 expression in subpopulations of cells in the embryonic hair placode. These subpopulations seem to act as precursors of different classes of adult epithelial stem cells. In particular, Runx1 regulates a Wnt-mediated cross-talk between the nascent adult-type hair follicle stem cells and their environment, which is essential for timely stem cell emergence, proper maturation, long-term differentiation potential, and maintenance. The new data begin to define the basic dynamics and regulatory pathways governing the ontogeny of adult epithelial stem cells.
Collapse
Affiliation(s)
- Tudorita Tumbar
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA,
| |
Collapse
|
|
21
|
Osorio KM, Lilja KC, Tumbar T. Runx1 modulates adult hair follicle stem cell emergence and maintenance from distinct embryonic skin compartments. ACTA ACUST UNITED AC 2011; 193:235-50. [PMID: 21464233 PMCID: PMC3082184 DOI: 10.1083/jcb.201006068] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Runx1 controls timing of adult HSFC and short-term progenitor emergence in the embryonic epithelium and HFSC differentiation and long-term skin integrity in embryonic mesenchyme. Runx1 controls hematopoietic stem cell emergence and hair follicle stem cell (HFSC) activation and proliferation in adult skin. Here we use lineage tracing and mouse genetic manipulation to address the role of Runx1 in the embryonic development of HFSCs. We find Runx1 is expressed in distinct classes of embryonic skin precursors for short-term HF progenitors, adult HFSCs, and mesenchymal progenitors. Runx1 acts in the embryonic epithelium for timely emergence of adult HFSCs and short-term progenitors, but is dispensable for both of them. In contrast, Runx1 is strictly needed in the embryonic mesenchyme for proper adult HFSC differentiation and long-term skin integrity. Our data implicate Runx1 in epithelial cell adhesion and migration and in regulation of paracrine epithelial–mesenchymal cross talk. The latter involves Lef1 and Wnt signaling modulation in opposing directions from two distinct skin compartments. Thus, a master regulator of hematopoiesis also controls HFSC emergence and maintenance via modulation of bidirectional cross talking between nascent stem cells and their niche.
Collapse
Affiliation(s)
- Karen M Osorio
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
| | | | | |
Collapse
|
|
22
|
Romano RA, Smalley K, Liu S, Sinha S. Abnormal hair follicle development and altered cell fate of follicular keratinocytes in transgenic mice expressing DeltaNp63alpha. Development 2010; 137:1431-9. [PMID: 20335364 DOI: 10.1242/dev.045427] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The transcription factor p63 plays an essential role in epidermal morphogenesis. Animals lacking p63 fail to form many ectodermal organs, including the skin and hair follicles. Although the indispensable role of p63 in stratified epithelial skin development is well established, relatively little is known about this transcriptional regulator in directing hair follicle morphogenesis. Here, using specific antibodies, we have established the expression pattern of DeltaNp63 in hair follicle development and cycling. DeltaNp63 is expressed in the developing hair placode, whereas in mature hair its expression is restricted to the outer root sheath (ORS), matrix cells and to the stem cells of the hair follicle bulge. To investigate the role of DeltaNp63 in hair follicle morphogenesis and cycling, we have utilized a Tet-inducible mouse model system with targeted expression of this isoform to the ORS of the hair follicle. DeltaNp63 transgenic animals display dramatic defects in hair follicle development and cycling, eventually leading to severe hair loss. Strikingly, expression of DeltaNp63 leads to a switch in cell fate of hair follicle keratinocytes, causing them to adopt an interfollicular epidermal (IFE) cell identity. Moreover, DeltaNp63 transgenic animals exhibit a depleted hair follicle stem-cell niche, which further contributes to the overall cycling defects observed in the mutant animals. Finally, global transcriptome analysis of transgenic skin identified altered expression levels of crucial mediators of hair morphogenesis, including key members of the Wnt/beta-catenin signaling pathway, which, in part, account for these effects. Our data provide evidence supporting a role for DeltaNp63alpha in actively suppressing hair follicle differentiation and directing IFE cell lineage commitment.
Collapse
Affiliation(s)
- Rose-Anne Romano
- Department of Biochemistry, Center for Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA
| | | | | | | |
Collapse
|
|
23
|
Runx1 directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse skin. Mol Cell Biol 2010; 30:2518-36. [PMID: 20308320 DOI: 10.1128/mcb.01308-09] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Runx1/AML1 is a transcription factor implicated in tissue stem cell regulation and belongs to the small Runx family of cancer genes. In the hair follicle (HF), Runx1 epithelial deletion in morphogenesis impairs normal adult hair homeostasis (cycle) and blocks adult hair follicle stem cells (HFSCs) in quiescence. Here, we show that these effects are overcome later in adulthood. By deleting Runx1 after the end of morphogenesis, we demonstrate its direct role in promoting anagen onset and HFSC proliferation. Runx1 deletion resulted in cyclin-dependent kinase inhibitor Cdkn1a (p21) upregulation. Interfering with Runx1 function in cultured HFSCs impaired their proliferation and normal G(0)/G1 and G(1)/S cell cycle progression. The proliferation defect could be rescued by Runx1 readdition or by p21 deletion. Chemically induced skin tumorigenesis in mice turned on broad Runx1 expression in regions of the skin epithelium, papillomas, and squamous cell carcinomas. In addition, it revealed reduced rates of tumor formation in the absence of Runx1 that were accompanied by decreased epithelial levels of phospho-Stat3. Runx1 protein expression was similar in normal human and mouse hair cycles. We propose that Runx1 may act as a skin oncogene by directly promoting proliferation of the epithelial cells.
Collapse
|
|
24
|
Philipot O, Joliot V, Ait-Mohamed O, Pellentz C, Robin P, Fritsch L, Ait-Si-Ali S. The core binding factor CBF negatively regulates skeletal muscle terminal differentiation. PLoS One 2010; 5:e9425. [PMID: 20195544 PMCID: PMC2828485 DOI: 10.1371/journal.pone.0009425] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2009] [Accepted: 02/03/2010] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Core Binding Factor or CBF is a transcription factor composed of two subunits, Runx1/AML-1 and CBF beta or CBFbeta. CBF was originally described as a regulator of hematopoiesis. METHODOLOGY/PRINCIPAL FINDINGS Here we show that CBF is involved in the control of skeletal muscle terminal differentiation. Indeed, downregulation of either Runx1 or CBFbeta protein level accelerates cell cycle exit and muscle terminal differentiation. Conversely, overexpression of CBFbeta in myoblasts slows terminal differentiation. CBF interacts directly with the master myogenic transcription factor MyoD, preferentially in proliferating myoblasts, via Runx1 subunit. In addition, we show a preferential recruitment of Runx1 protein to MyoD target genes in proliferating myoblasts. The MyoD/CBF complex contains several chromatin modifying enzymes that inhibits MyoD activity, such as HDACs, Suv39h1 and HP1beta. When overexpressed, CBFbeta induced an inhibition of activating histone modification marks concomitant with an increase in repressive modifications at MyoD target promoters. CONCLUSIONS/SIGNIFICANCE Taken together, our data show a new role for Runx1/CBFbeta in the control of the proliferation/differentiation in skeletal myoblasts.
Collapse
Affiliation(s)
- Ophélie Philipot
- Institut André Lwoff, FRE2944, CNRS and Université Paris-Sud, Villejuif, France
| | - Véronique Joliot
- Institut André Lwoff, FRE2944, CNRS and Université Paris-Sud, Villejuif, France
| | - Ouardia Ait-Mohamed
- Institut André Lwoff, FRE2944, CNRS and Université Paris-Sud, Villejuif, France
| | - Céline Pellentz
- Institut André Lwoff, FRE2944, CNRS and Université Paris-Sud, Villejuif, France
| | - Philippe Robin
- Institut André Lwoff, FRE2944, CNRS and Université Paris-Sud, Villejuif, France
| | - Lauriane Fritsch
- Institut André Lwoff, FRE2944, CNRS and Université Paris-Sud, Villejuif, France
| | - Slimane Ait-Si-Ali
- Institut André Lwoff, FRE2944, CNRS and Université Paris-Sud, Villejuif, France
- * E-mail:
| |
Collapse
|
|
25
|
Wang CQ, Jacob B, Nah GSS, Osato M. Runx family genes, niche, and stem cell quiescence. Blood Cells Mol Dis 2010; 44:275-86. [PMID: 20144877 DOI: 10.1016/j.bcmd.2010.01.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2010] [Accepted: 01/05/2010] [Indexed: 02/07/2023]
Abstract
In multicellular organisms, terminally differentiated cells of most tissues are short-lived and therefore require constant replenishment from rapidly dividing stem cells for homeostasis and tissue repair. For the stem cells to last throughout the lifetime of the organism, however, a small subset of stem cells, which are maintained in a hibernation-like state known as stem cell quiescence, is required. Such dormant stem cells reside in the niche and are activated into proliferation only when necessary. A multitude of factors are required for the maintenance of stem cell quiescence and niche. In particular, the Runx family genes have been implicated in stem cell quiescence in various organisms and tissues. In this review, we discuss the maintenance of stem cell quiescence in various tissues, mainly in the context of the Runx family genes, and with special focus on the hematopoietic system.
Collapse
Affiliation(s)
- Chelsia Qiuxia Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | | | | | | |
Collapse
|
|
26
|
|
|
27
|
Duverger O, Morasso MI. Epidermal patterning and induction of different hair types during mouse embryonic development. BIRTH DEFECTS RESEARCH. PART C, EMBRYO TODAY : REVIEWS 2009; 87:263-72. [PMID: 19750518 PMCID: PMC2995294 DOI: 10.1002/bdrc.20158] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
An intriguing question in developmental biology is how epidermal pattern formation processes are established and what are the molecular mechanisms involved in these events. The establishment of the pattern is concomitant with the formation of ectodermal appendages, which involves complex interactions between the epithelium and the underlying mesenchyme. Among ectodermal appendages, hair follicles are the "mini organs" that produce hair shafts. Several developmental and structural features are common to all hair follicles and to the hair shaft they produce. However, many different hair types are produced in a single organism. Also, different characteristics can be observed depending on the part of the body where the hair follicle is formed. Here, we review the mechanisms involved in the patterning of different hair types during mouse embryonic development as well as the influence of the body axes on hair patterning.
Collapse
Affiliation(s)
- Olivier Duverger
- Developmental Skin Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA
| | | |
Collapse
|
|
28
|
Yu Z, Gordon SW, Nixon AJ, Bawden CS, Rogers MA, Wildermoth JE, Maqbool NJ, Pearson AJ. Expression patterns of keratin intermediate filament and keratin associated protein genes in wool follicles. Differentiation 2008; 77:307-16. [PMID: 19272529 DOI: 10.1016/j.diff.2008.10.009] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2008] [Revised: 09/17/2008] [Accepted: 10/03/2008] [Indexed: 10/20/2022]
Abstract
The catalogue of hair keratin intermediate filaments (KIFs) and keratin-associated proteins (KAPs) present in wool follicles is incomplete. The full coding sequences for three novel sheep KIFs (KRT27, KRT35 and KRT38) and one KAP (KRTAP4-3) were established in this study. Spatial expression patterns of these and other genes (KRT31, KRT85, KRTAP6-1 and trichohyalin) were determined by in situ hybridisation in wool follicles at synchronised stages of growth. Transcription proceeded in the order: trichohyalin, KRT27, KRT85, KRT35, KRT31, KRT38, KRTAP6-1 and KRTAP4-3, as determined by increasing distance of their expression zones from the germinal matrix in anagen follicles. Expression became gradually more restricted to the lower follicle during follicle regression (catagen), and ceased during dormancy (telogen). Some genes (KRT27, KRT31, KRT85 and KRTAP6-1), but not others, were expressed in cortical cells forming the brush-end, indicating specific requirements for the formation of this anchoring structure. The resumption of keratin expression was observed only in later stages of follicle reactivation (proanagen). KIF expression patterns in primary wool follicles showed general resemblance to their human homologues but with some unique features. Consistent differences in localisation between primary and secondary wool follicles were observed. Asymmetrical expression of KRT27, KRT31, KRT35, KRT85 and trichohyalin genes in secondary follicles were associated with bulb deflection and follicle curvature, suggesting a role in the determination of follicle and fibre morphology.
Collapse
Affiliation(s)
- Zhidong Yu
- Growth and Development Section, AgResearch Ruakura, Private Bag 3123, Hamilton 3214, New Zealand.
| | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Robertson AJ, Coluccio A, Knowlton P, Dickey-Sims C, Coffman JA. Runx expression is mitogenic and mutually linked to Wnt activity in blastula-stage sea urchin embryos. PLoS One 2008; 3:e3770. [PMID: 19020668 PMCID: PMC2582955 DOI: 10.1371/journal.pone.0003770] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2008] [Accepted: 11/01/2008] [Indexed: 11/25/2022] Open
Abstract
Background The Runt homology domain (Runx) defines a metazoan family of sequence-specific transcriptional regulatory proteins that are critical for animal development and causally associated with a variety of mammalian cancers. The sea urchin Runx gene SpRunt-1 is expressed throughout the blastula stage embryo, and is required globally during embryogenesis for cell survival and differentiation. Methodology/Principal Findings Depletion of SpRunt-1 by morpholino antisense-mediated knockdown causes a blastula stage deficit in cell proliferation, as shown by bromodeoxyuridine (BrdU) incorporation and direct cell counts. Reverse transcription coupled polymerase chain reaction (RT-PCR) studies show that the cell proliferation deficit is presaged by a deficit in the expression of several zygotic wnt genes, including wnt8, a key regulator of endomesoderm development. In addition, SpRunt-1-depleted blastulae underexpress cyclinD, an effector of mitogenic Wnt signaling. Blastula stage cell proliferation is also impeded by knockdown of either wnt8 or cyclinD. Chromatin immunoprecipitation (ChIP) indicates that Runx target sites within 5′ sequences flanking cyclinD, wnt6 and wnt8 are directly bound by SpRunt-1 protein at late blastula stage. Furthermore, experiments using a green fluorescent protein (GFP) reporter transgene show that the blastula-stage operation of a cis-regulatory module previously shown to be required for wnt8 expression (Minokawa et al., Dev. Biol. 288: 545–558, 2005) is dependent on its direct sequence-specific interaction with SpRunt-1. Finally, inhibitor studies and immunoblot analysis show that SpRunt-1 protein levels are negatively regulated by glycogen synthase kinase (GSK)-3. Conclusions/Significance These results suggest that Runx expression and Wnt signaling are mutually linked in a feedback circuit that controls cell proliferation during development.
Collapse
Affiliation(s)
- Anthony J. Robertson
- Mount Desert Island Biological Laboratory, Salisbury Cove, Maine, United States of America
| | - Alison Coluccio
- Mount Desert Island Biological Laboratory, Salisbury Cove, Maine, United States of America
| | - Peter Knowlton
- Mount Desert Island Biological Laboratory, Salisbury Cove, Maine, United States of America
| | - Carrie Dickey-Sims
- Stowers Institute for Medical Research, Kansas City, Missouri, United States of America
| | - James A. Coffman
- Mount Desert Island Biological Laboratory, Salisbury Cove, Maine, United States of America
- * E-mail:
| |
Collapse
|
|
30
|
Charoenchaikorn K, Yokomizo T, Rice DP, Honjo T, Matsuzaki K, Shintaku Y, Imai Y, Wakamatsu A, Takahashi S, Ito Y, Takano-Yamamoto T, Thesleff I, Yamamoto M, Yamashiro T. Runx1 is involved in the fusion of the primary and the secondary palatal shelves. Dev Biol 2008; 326:392-402. [PMID: 19000669 DOI: 10.1016/j.ydbio.2008.10.018] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2008] [Revised: 09/15/2008] [Accepted: 10/13/2008] [Indexed: 11/19/2022]
Abstract
Runx1 is expressed in medial edge epithelial (MEE) cells of the palatal shelf. Conditionally rescued Runx1(-/-) mice showed limited clefting in the anterior junction between the primary and the secondary palatal shelves, but not in the junction between the secondary palates. In wild type mice, the fusing epithelial surface exhibited a rounded cobblestone-like appearance, while such cellular prominence was less evident in the Runx1 mutants. We also found that Fgf18 was expressed in the mesenchyme underlying the MEE and that locally applied FGF18 induced ectopic Runx1 expression in the epithelium of the palatal explants, indicating that Runx1 was induced by mesenchymal Fgf18 signaling. On the other hand, unpaired palatal explant cultures revealed the presence of anterior-posterior (A-P) differences in the MEE fates and fusion mechanism. Interestingly, the location of anterior clefting in Runx1 mutants corresponded to the region with different MEE behavior. These data showed a novel function of Runx1 in morphological changes in the MEE cells in palatal fusion, which is, at least in part, regulated by the mesenchymal Fgf signaling via an epithelial-mesenchymal interaction.
Collapse
Affiliation(s)
- Kesinee Charoenchaikorn
- Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Suita, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Ortt K, Raveh E, Gat U, Sinha S. A chromatin immunoprecipitation screen in mouse keratinocytes reveals Runx1 as a direct transcriptional target of DeltaNp63. J Cell Biochem 2008; 104:1204-19. [PMID: 18275068 DOI: 10.1002/jcb.21700] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Development of the skin epidermis and appendages such as hair follicles involves coordinated processes of keratinocyte proliferation and differentiation. The transcription factor p63 plays a critical role in these steps as evident by a complete lack of these structures in p63 null mice. The p63 gene encodes for two proteins TAp63 and DeltaNp63, the latter being the more prevalent and dominant isoform expressed in keratinocytes. Although numerous p63 target genes have been identified, these studies have been limited to transformed human keratinocyte cell lines. Here, we have employed a genomic screening approach of chromatin immunoprecipitation (ChIP) coupled with an enrichment strategy to identify DeltaNp63 response elements in primary mouse keratinocytes. Analysis of p63-ChIP-derived DNA segments has revealed more than 100 potential target genes including novel as well as mouse counterparts of established human p63 targets. Among these is Runx1, a transcription factor important for hair follicle development. We demonstrate that DeltaNp63 binds to a p63-response element located within a well-conserved enhancer of the Runx1 gene. Furthermore, siRNA mediated reduction of DeltaNp63 in mouse keratinocytes reduces Runx1 expression. Consistent with this, endogenous Runx1 levels are lower in the skin of p63(+/-) animals as compared to wild type animals. Lastly, we demonstrate that DeltaNp63 and Runx1 are co-expressed in specific compartments of the hair follicle in a dynamic fashion. Taken together our data demonstrate that p63 directly regulates Runx1 gene expression through a novel enhancer element and suggests a role for these two transcription factors in dictating skin keratinocyte and appendage development.
Collapse
Affiliation(s)
- Kori Ortt
- Department of Biochemistry, State University of New York at Buffalo, Buffalo, New York 14214, USA
| | | | | | | |
Collapse
|
|
32
|
Sullivan JC, Sher D, Eisenstein M, Shigesada K, Reitzel AM, Marlow H, Levanon D, Groner Y, Finnerty JR, Gat U. The evolutionary origin of the Runx/CBFbeta transcription factors--studies of the most basal metazoans. BMC Evol Biol 2008; 8:228. [PMID: 18681949 PMCID: PMC2527000 DOI: 10.1186/1471-2148-8-228] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2008] [Accepted: 08/05/2008] [Indexed: 11/17/2022] Open
Abstract
Background Members of the Runx family of transcriptional regulators, which bind DNA as heterodimers with CBFβ, are known to play critical roles in embryonic development in many triploblastic animals such as mammals and insects. They are known to regulate basic developmental processes such as cell fate determination and cellular potency in multiple stem-cell types, including the sensory nerve cell progenitors of ganglia in mammals. Results In this study, we detect and characterize the hitherto unexplored Runx/CBFβ genes of cnidarians and sponges, two basal animal lineages that are well known for their extensive regenerative capacity. Comparative structural modeling indicates that the Runx-CBFβ-DNA complex from most cnidarians and sponges is highly similar to that found in humans, with changes in the residues involved in Runx-CBFβ dimerization in either of the proteins mirrored by compensatory changes in the binding partner. In situ hybridization studies reveal that Nematostella Runx and CBFβ are expressed predominantly in small isolated foci at the base of the ectoderm of the tentacles in adult animals, possibly representing neurons or their progenitors. Conclusion These results reveal that Runx and CBFβ likely functioned together to regulate transcription in the common ancestor of all metazoans, and the structure of the Runx-CBFβ-DNA complex has remained extremely conserved since the human-sponge divergence. The expression data suggest a hypothesis that these genes may have played a role in nerve cell differentiation or maintenance in the common ancestor of cnidarians and bilaterians.
Collapse
Affiliation(s)
- James C Sullivan
- Department of Biology, Boston University, 5 Cummington St, Boston, MA 02215, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Li SW, Ouyang HS, Rogers GE, Bawden CS. Characterization of the structural and molecular defects in fibres and follicles of the Merino felting lustre mutant. Exp Dermatol 2008; 18:134-42. [PMID: 18637126 DOI: 10.1111/j.1600-0625.2008.00774.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The felting lustre (FL) mutation found in Merino sheep results in a fleece that has a lustrous appearance and readily felts. This phenotype was described 50 years ago to result from the mutation of a single gene, but the molecular and cellular changes in the wool are not well understood. In this study, follicle and fibre material of FL mutant (n = 3) and normal control (n = 5) Merino ewes was compared using histological analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), real-time polymerase chain reaction (qPCR) and electron microscopy [scanning electron microscopy (SEM) and transmission electron microscopy (TEM)]. Histological examination suggested that follicle structure in FL mutants is essentially normal, while SDS-PAGE analysis found that some low molecular weight keratin-associated proteins (KAP) were present at much lower levels in FL wool. Examination of transcript prevalence revealed that the KAP6.1, KAP7 and KAP8 genes in FL mutant follicles are downregulated, while the KAP2.12 and KAP4.2 genes are upregulated. TEM analysis indicated that there is only one type of cortical cell, the paracortical cell, in the fibre of FL mutants, while there are paracortical and orthocortical cells in fibres of normal Merino sheep. In contrast, SEM suggested the surface topography of FL wool fibres is normal. The evidence presented here strongly suggests that the properties of FL wool can be ascribed, at least in part, to the lower content of high glycine/tyrosine proteins and the reduction in orthocortical cells in mutant wool fibres.
Collapse
Affiliation(s)
- Shu Wei Li
- College of Animal Science & Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | | | | | | |
Collapse
|
|
34
|
Osorio KM, Lee SE, McDermitt DJ, Waghmare SK, Zhang YV, Woo HN, Tumbar T. Runx1 modulates developmental, but not injury-driven, hair follicle stem cell activation. Development 2008; 135:1059-68. [PMID: 18256199 DOI: 10.1242/dev.012799] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Aml1/Runx1 controls developmental aspects of several tissues, is a master regulator of blood stem cells, and plays a role in leukemia. However, it is unclear whether it functions in tissue stem cells other than blood. Here, we have investigated the role of Runx1 in mouse hair follicle stem cells by conditional ablation in epithelial cells. Runx1 disruption affects hair follicle stem cell activation, but not their maintenance, proliferation or differentiation potential. Adult mutant mice exhibit impaired de novo production of hair shafts and all temporary hair cell lineages, owing to a prolonged quiescent phase of the first hair cycle. The lag of stem cell activity is reversed by skin injury. Our work suggests a degree of functional overlap in Runx1 regulation of blood and hair follicle stem cells at an equivalent time point in the development of these two tissues.
Collapse
Affiliation(s)
- Karen M Osorio
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
| | | | | | | | | | | | | |
Collapse
|
|
35
|
Impaired skin and hair follicle development in Runx2 deficient mice. Dev Biol 2008; 315:459-73. [PMID: 18262513 PMCID: PMC2280036 DOI: 10.1016/j.ydbio.2008.01.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2007] [Revised: 12/11/2007] [Accepted: 01/03/2008] [Indexed: 11/20/2022]
Abstract
The transcription factor, Runx2, is known to play crucial roles in skeletal and tooth morphogenesis. Here we document that Runx2 has a regulatory role in skin and hair follicle development. The expression of Runx2 is restricted to hair follicles and is dynamic, pari passu with follicle development. Follicle maturation is delayed in the absence of Runx2 and overall skin and epidermal thickness of Runx2 null embryos is significantly reduced. The Runx2 null epidermis is hypoplastic, displaying reduced expression of Keratin 14, Keratin 1 and markers of proliferation. The expression pattern of Runx2 in the bulb epithelium of mature hair follicles is asymmetric and strikingly similar to that of Sonic hedgehog. This suggests that Runx2 may be a regulator of hedgehog signaling in skin as it is in bones and teeth. Supporting this possibility, we demonstrate that Sonic hedgehog, Patched1 and Gli1 transcripts are reduced in the skin of Runx2 null embryos. Moreover, we document Patched1 expression in epidermal basal cells and show that the skin of Sonic(+/-) embryos is thinner than that of wild-type littermates. These observations suggest that Runx2 and hedgehog signaling are involved in the well known, but unexplained, coupling of skin thickness to hair follicle development.
Collapse
|