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Castro Colabianchi AM, González Pérez NG, Franchini LF, López SL. A maternal dorsoventral prepattern revealed by an asymmetric distribution of ventralizing molecules before fertilization in Xenopus laevis. Front Cell Dev Biol 2024; 12:1365705. [PMID: 38572484 PMCID: PMC10987785 DOI: 10.3389/fcell.2024.1365705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 03/07/2024] [Indexed: 04/05/2024] Open
Abstract
The establishment of the embryonic dorsoventral axis in Xenopus occurs when the radial symmetry around the egg's animal-vegetal axis is broken to give rise to the typical symmetry of Bilaterians. We have previously shown that the Notch1 protein is ventrally enriched during early embryogenesis in Xenopus laevis and zebrafish and exerts ventralizing activity through β-Catenin destabilization and the positive regulation of ventral center genes in X. laevis. These findings led us to further investigate when these asymmetries arise. In this work, we show that the asymmetrical distribution of Notch1 protein and mRNA precedes cortical rotation and even fertilization in X. laevis. Moreover, we found that in unfertilized eggs transcripts encoded by the ventralizing gene bmp4 are also asymmetrically distributed in the animal hemisphere and notch1 transcripts accumulate consistently on the same side of the eccentric maturation point. Strikingly, a Notch1 asymmetry orthogonal to the animal-vegetal axis appears during X. laevis oogenesis. Thus, we show for the first time a maternal bias in the distribution of molecules that are later involved in ventral patterning during embryonic axialization, strongly supporting the hypothesis of a dorsoventral prepattern or intrinsic bilaterality of Xenopus eggs before fertilization.
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Affiliation(s)
- Aitana M. Castro Colabianchi
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular e Histología / 1° U.A. Departamento de Histología, Embriología, Biología Celular y Genética, Laboratorio de Embriología Molecular “Prof. Dr. Andrés E. Carrasco”, Buenos Aires, Argentina
- CONICET–Universidad de Buenos Aires, Instituto de Biología Celular y Neurociencias “Prof. E. De Robertis” (IBCN), Buenos Aires, Argentina
| | - Nicolás G. González Pérez
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular e Histología / 1° U.A. Departamento de Histología, Embriología, Biología Celular y Genética, Laboratorio de Embriología Molecular “Prof. Dr. Andrés E. Carrasco”, Buenos Aires, Argentina
- CONICET–Universidad de Buenos Aires, Instituto de Biología Celular y Neurociencias “Prof. E. De Robertis” (IBCN), Buenos Aires, Argentina
| | - Lucía F. Franchini
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI) “Dr. Héctor N. Torres”, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Silvia L. López
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular e Histología / 1° U.A. Departamento de Histología, Embriología, Biología Celular y Genética, Laboratorio de Embriología Molecular “Prof. Dr. Andrés E. Carrasco”, Buenos Aires, Argentina
- CONICET–Universidad de Buenos Aires, Instituto de Biología Celular y Neurociencias “Prof. E. De Robertis” (IBCN), Buenos Aires, Argentina
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2
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Gao J, Lu Y, Luo Y, Duan X, Chen P, Zhang X, Wu X, Qiu M, Shen W. β-Catenin and SOX2 Interaction Regulate Visual Experience-Dependent Cell Homeostasis in the Developing Xenopus Thalamus. Int J Mol Sci 2023; 24:13593. [PMID: 37686400 PMCID: PMC10488257 DOI: 10.3390/ijms241713593] [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: 07/31/2023] [Revised: 08/19/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
In the vertebrate brain, sensory experience plays a crucial role in shaping thalamocortical connections for visual processing. However, it is still not clear how visual experience influences tissue homeostasis and neurogenesis in the developing thalamus. Here, we reported that the majority of SOX2-positive cells in the thalamus are differentiated neurons that receive visual inputs as early as stage 47 Xenopus. Visual deprivation (VD) for 2 days shifts the neurogenic balance toward proliferation at the expense of differentiation, which is accompanied by a reduction in nuclear-accumulated β-catenin in SOX2-positive neurons. The knockdown of β-catenin decreases the expression of SOX2 and increases the number of progenitor cells. Coimmunoprecipitation studies reveal the evolutionary conservation of strong interactions between β-catenin and SOX2. These findings indicate that β-catenin interacts with SOX2 to maintain homeostatic neurogenesis during thalamus development.
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Affiliation(s)
- Juanmei Gao
- Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China (M.Q.)
- College of Life and Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yufang Lu
- Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China (M.Q.)
| | - Yuhao Luo
- Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China (M.Q.)
| | - Xinyi Duan
- Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China (M.Q.)
| | - Peiyao Chen
- Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China (M.Q.)
| | - Xinyu Zhang
- Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China (M.Q.)
| | - Xiaohua Wu
- Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China (M.Q.)
| | - Mengsheng Qiu
- Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China (M.Q.)
- College of Life and Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wanhua Shen
- Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China (M.Q.)
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Favarolo MB, Revinski DR, Garavaglia MJ, López SL. Nodal and churchill1 position the expression of a notch ligand during Xenopus germ layer segregation. Life Sci Alliance 2022; 5:5/12/e202201693. [PMID: 36180230 PMCID: PMC9604498 DOI: 10.26508/lsa.202201693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/24/2022] Open
Abstract
Churchill and Nodal signaling, which participate in vertebrates’ germ layer induction, position a domain of Delta/Notch activity, which refines germ layer boundaries during frog gastrulation. In vertebrates, Nodal signaling plays a major role in endomesoderm induction, but germ layer delimitation is poorly understood. In avian embryos, the neural/mesoderm boundary is controlled by the transcription factor CHURCHILL1, presumably through the repressor ZEB2, but there is scarce knowledge about its role in other vertebrates. During amphibian gastrulation, Delta/Notch signaling refines germ layer boundaries in the marginal zone, but it is unknown the place this pathway occupies in the network comprising Churchill1 and Nodal. Here, we show that Xenopus churchill1 is expressed in the presumptive neuroectoderm at mid-blastula transition and during gastrulation, upregulates zeb2, prevents dll1 expression in the neuroectoderm, and favors neuroectoderm over endomesoderm development. Nodal signaling prevents dll1 expression in the endoderm but induces it in the presumptive mesoderm, from where it activates Notch1 and its target gene hes4 in the non-involuting marginal zone. We propose a model where Nodal and Churchill1 position Dll1/Notch1/Hes4 domains in the marginal zone, ensuring the delimitation between mesoderm and neuroectoderm.
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Affiliation(s)
- María Belén Favarolo
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular e Histología/1° U.A. Departamento de Histología, Embriología, Biología Celular y Genética, Buenos Aires, Argentina.,CONICET-Universidad de Buenos Aires, Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis" (IBCN), Laboratorio de Embriología Molecular "Prof. Dr. Andrés E. Carrasco", Buenos Aires, Argentina
| | - Diego R Revinski
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular e Histología/1° U.A. Departamento de Histología, Embriología, Biología Celular y Genética, Buenos Aires, Argentina.,CONICET-Universidad de Buenos Aires, Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis" (IBCN), Laboratorio de Embriología Molecular "Prof. Dr. Andrés E. Carrasco", Buenos Aires, Argentina
| | - Matías J Garavaglia
- Laboratorio de Bioinsumos, Instituto de Biotecnología, Universidad Nacional de Hurlingham, Buenos Aires, Argentina
| | - Silvia L López
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular e Histología/1° U.A. Departamento de Histología, Embriología, Biología Celular y Genética, Buenos Aires, Argentina .,CONICET-Universidad de Buenos Aires, Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis" (IBCN), Laboratorio de Embriología Molecular "Prof. Dr. Andrés E. Carrasco", Buenos Aires, Argentina
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4
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Swoboda J, Mittelsdorf P, Chen Y, Weiskirchen R, Stallhofer J, Schüle S, Gassler N. Intestinal Wnt in the transition from physiology to oncology. World J Clin Oncol 2022; 13:168-185. [PMID: 35433295 PMCID: PMC8966512 DOI: 10.5306/wjco.v13.i3.168] [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: 02/23/2021] [Revised: 09/07/2021] [Accepted: 02/19/2022] [Indexed: 02/06/2023] Open
Abstract
Adult stem cells are necessary for self-renewal tissues and regeneration after damage. Especially in the intestine, which self-renews every few days, they play a key role in tissue homeostasis. Therefore, complex regulatory mechanisms are needed to prevent hyperproliferation, which can lead in the worst case to carcinogenesis or under-activation of stem cells, which can result in dysfunctional epithelial. One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway. It is a highly conserved pathway, with β-catenin, a transcription factor, as target protein. Translocation of β-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripo-tency, proliferation, cell differentiation and regulation of cell death. This review presents a brief overview of the Wnt/β-catenin signaling pathway, the regulatory mechanism of this pathway and its role in intestinal homeostasis. Additionally, this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation. Furthermore, the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.
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Affiliation(s)
- Julia Swoboda
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Patrick Mittelsdorf
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Johannes Stallhofer
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena 07747, Germany
| | - Silke Schüle
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
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5
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Miyamoto M, Andersen P, Sulistio E, Liu X, Murphy S, Kannan S, Nam L, Miyamoto W, Tampakakis E, Hibino N, Uosaki H, Kwon C. Noncanonical Notch signals have opposing roles during cardiac development. Biochem Biophys Res Commun 2021; 577:12-16. [PMID: 34487959 PMCID: PMC8484041 DOI: 10.1016/j.bbrc.2021.08.094] [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: 08/10/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 10/20/2022]
Abstract
The Notch pathway is an ancient intercellular signaling system with crucial roles in numerous cell-fate decision processes across species. While the canonical pathway is activated by ligand-induced cleavage and nuclear localization of membrane-bound Notch, Notch can also exert its activity in a ligand/transcription-independent fashion, which is conserved in Drosophila, Xenopus, and mammals. However, the noncanonical role remains poorly understood in in vivo processes. Here we show that increased levels of the Notch intracellular domain (NICD) in the early mesoderm inhibit heart development, potentially through impaired induction of the second heart field (SHF), independently of the transcriptional effector RBP-J. Similarly, inhibiting Notch cleavage, shown to increase noncanonical Notch activity, suppressed SHF induction in embryonic stem cell (ESC)-derived mesodermal cells. In contrast, NICD overexpression in late cardiac progenitor cells lacking RBP-J resulted in an increase in heart size. Our study suggests that noncanonical Notch signaling has stage-specific roles during cardiac development.
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Affiliation(s)
- Matthew Miyamoto
- Division of Cardiology, Department of Medicine, Johns Hopkins University Baltimore, MD,Heart and Vascular Institute, Cellular and Molecular Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Biomedical Engineering, Department of Cell Biology, Johns Hopkins University Baltimore, MD
| | - Peter Andersen
- Division of Cardiology, Department of Medicine, Johns Hopkins University Baltimore, MD,Heart and Vascular Institute, Cellular and Molecular Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Biomedical Engineering, Department of Cell Biology, Johns Hopkins University Baltimore, MD
| | - Edrick Sulistio
- Division of Cardiology, Department of Medicine, Johns Hopkins University Baltimore, MD,Heart and Vascular Institute, Cellular and Molecular Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Biomedical Engineering, Department of Cell Biology, Johns Hopkins University Baltimore, MD
| | - Xihe Liu
- Division of Cardiology, Department of Medicine, Johns Hopkins University Baltimore, MD,Heart and Vascular Institute, Cellular and Molecular Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Biomedical Engineering, Department of Cell Biology, Johns Hopkins University Baltimore, MD
| | - Sean Murphy
- Division of Cardiology, Department of Medicine, Johns Hopkins University Baltimore, MD,Heart and Vascular Institute, Cellular and Molecular Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Biomedical Engineering, Department of Cell Biology, Johns Hopkins University Baltimore, MD
| | - Suraj Kannan
- Division of Cardiology, Department of Medicine, Johns Hopkins University Baltimore, MD,Heart and Vascular Institute, Cellular and Molecular Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Biomedical Engineering, Department of Cell Biology, Johns Hopkins University Baltimore, MD
| | - Lucy Nam
- Division of Cardiology, Department of Medicine, Johns Hopkins University Baltimore, MD,Heart and Vascular Institute, Cellular and Molecular Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Biomedical Engineering, Department of Cell Biology, Johns Hopkins University Baltimore, MD,Present address: Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - William Miyamoto
- Division of Cardiology, Department of Medicine, Johns Hopkins University Baltimore, MD,Heart and Vascular Institute, Cellular and Molecular Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Biomedical Engineering, Department of Cell Biology, Johns Hopkins University Baltimore, MD
| | - Emmanouil Tampakakis
- Division of Cardiology, Department of Medicine, Johns Hopkins University Baltimore, MD,Heart and Vascular Institute, Cellular and Molecular Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Narutoshi Hibino
- Department of Surgery, The University of Chicago Medical Center, Chicago, IL
| | - Hideki Uosaki
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Chulan Kwon
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA; Heart and Vascular Institute, Cellular and Molecular Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Department of Cell Biology, Johns Hopkins University, Baltimore, MD, USA.
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6
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Acar A, Hidalgo-Sastre A, Leverentz MK, Mills CG, Woodcock S, Baron M, Collu GM, Brennan K. Inhibition of Wnt signalling by Notch via two distinct mechanisms. Sci Rep 2021; 11:9096. [PMID: 33907274 PMCID: PMC8079408 DOI: 10.1038/s41598-021-88618-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 03/03/2021] [Indexed: 12/30/2022] Open
Abstract
Notch and Wnt are two essential signalling pathways that help to shape animals during development and to sustain adult tissue homeostasis. Although they are often active at the same time within a tissue, they typically have opposing effects on cell fate decisions. In fact, crosstalk between the two pathways is important in generating the great diversity of cell types that we find in metazoans. Several different mechanisms have been proposed that allow Notch to limit Wnt signalling, driving a Notch-ON/Wnt-OFF state. Here we explore these different mechanisms in human cells and demonstrate two distinct mechanisms by which Notch itself, can limit the transcriptional activity of β-catenin. At the membrane, independently of DSL ligands, Notch1 can antagonise β-catenin activity through an endocytic mechanism that requires its interaction with Deltex and sequesters β-catenin into the membrane fraction. Within the nucleus, the intracellular domain of Notch1 can also limit β-catenin induced transcription through the formation of a complex that requires its interaction with RBPjκ. We believe these mechanisms contribute to the robustness of cell-fate decisions by sharpening the distinction between opposing Notch/Wnt responses.
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Affiliation(s)
- Ahmet Acar
- Department of Biological Sciences, Middle East Technical University, Universiteler Mah. Dumlupınar Bulvarı 1, 06800, Çankaya, Ankara, Turkey.
- Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
| | - Ana Hidalgo-Sastre
- Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
| | - Michael K Leverentz
- Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
| | - Christopher G Mills
- Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
| | - Simon Woodcock
- Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
| | - Martin Baron
- Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
| | - Giovanna M Collu
- Department of Developmental and Regenerative Biology, Icahn School of Medicine At Mount Sinai, One Gustave L. Levy Place, Box 1020, New York, NY, 10029, USA
| | - Keith Brennan
- Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
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Gao J, Fan L, Zhao L, Su Y. The interaction of Notch and Wnt signaling pathways in vertebrate regeneration. CELL REGENERATION (LONDON, ENGLAND) 2021; 10:11. [PMID: 33791915 PMCID: PMC8012441 DOI: 10.1186/s13619-020-00072-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 12/14/2020] [Indexed: 12/21/2022]
Abstract
Regeneration is an evolutionarily conserved process in animal kingdoms, however, the regenerative capacities differ from species and organ/tissues. Mammals possess very limited regenerative potential to replace damaged organs, whereas non-mammalian species usually have impressive abilities to regenerate organs. The regeneration process requires proper spatiotemporal regulation from key signaling pathways. The canonical Notch and Wnt signaling pathways, two fundamental signals guiding animal development, have been demonstrated to play significant roles in the regeneration of vertebrates. In recent years, increasing evidence has implicated the cross-talking between Notch and Wnt signals during organ regeneration. In this review, we summarize the roles of Notch signaling and Wnt signaling during several representative organ regenerative events, emphasizing the functions and molecular bases of their interplay in these processes, shedding light on utilizing these two signaling pathways to enhance regeneration in mammals and design legitimate therapeutic strategies.
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Affiliation(s)
- Junying Gao
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, Shandong, China.,College of Fisheries, Ocean University of China, Qingdao, 266003, Shandong, China
| | - Lixia Fan
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, Shandong, China.,College of Fisheries, Ocean University of China, Qingdao, 266003, Shandong, China
| | - Long Zhao
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, Shandong, China. .,College of Fisheries, Ocean University of China, Qingdao, 266003, Shandong, China.
| | - Ying Su
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, Shandong, China. .,College of Marine Life Sciences, Ocean University of China, Qingdao, 266003, Shandong, China.
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8
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Saini N, Sarin A. Nucleolar localization of the Notch4 intracellular domain underpins its regulation of the cellular response to genotoxic stressors. Cell Death Discov 2020; 6:7. [PMID: 32123583 PMCID: PMC7029026 DOI: 10.1038/s41420-020-0242-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/01/2020] [Accepted: 02/03/2020] [Indexed: 02/07/2023] Open
Abstract
Cell survival is one of the many cellular processes regulated by Notch family of proteins. A comparison of human breast cancer cell lines, which differ in the levels of endogenous Notch4, implicated the protein in regulating susceptibility to apoptosis triggered by genomic damage. In agreement with this observation, increased susceptibility to genotoxic damage was observed following siRNA ablations of Notch4 in two breast cancer cell lines. Further, overexpressing Notch4 intracellular domain (NIC4) tagged to GFP (NIC4-GFP), protected cells from apoptosis triggered by genotoxic drugs. In cells immune-stained for endogenous Notch4, protein was detected in the nucleolus and nucleoplasm, which was also confirmed by the co-localization of NIC4-GFP with RFP-tagged nucleolar proteins in breast cancer cells or the unrelated HEK cell line. Linking functional outcomes to nucleolar localization, NIC4-GFP protection from apoptosis, required the nucleolar proteins Nucleolin and Fibrillarin. Consistently, immunoprecipitation analysis revealed associations between nucleolar proteins-Nucleolin and Nucleophosmin-and Notch4. Microscopy-based biophysical analysis of live cells showed that nucleolar and nucleoplasmic pools of NIC4-GFP are mobile, with some sequestration of nucleolar NIC4-GFP pools. A nucleolar excluded form, NIC4_3RA-GFP, generated by site-directed mutagenesis of the nucleolar localization sequence in NIC4, could not protect from apoptosis triggered by genotoxic stressors. However, transcriptional activity or protection from apoptosis triggered by endoplasmic stress was comparable in cells expressing NIC4_3RA-GFP or NIC4-GFP. Together, the data show that nucleolar localization of NIC4 is critical for the regulation of genomic damage and may be uncoupled from its activities in the nucleoplasm. This study identifies intrinsic features of NIC4 that regulate signaling outcomes activated by the receptor by controlling its spatial localization.
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Affiliation(s)
- Neetu Saini
- Institute for Stem Cell Science & Regenerative Medicine (inStem), Bellary Road, Bengaluru, Karnataka India
- Department of Biology, Manipal Academy of Higher Education, Manipal, India
| | - Apurva Sarin
- Institute for Stem Cell Science & Regenerative Medicine (inStem), Bellary Road, Bengaluru, Karnataka India
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9
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Goto T, Kanda K, Nishikata T. Non-centrosomal microtubule structures regulated by egg activation signaling contribute to cytoplasmic and cortical reorganization in the ascidian egg. Dev Biol 2018; 448:161-172. [PMID: 31030741 DOI: 10.1016/j.ydbio.2018.10.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 10/10/2018] [Accepted: 10/17/2018] [Indexed: 10/28/2022]
Abstract
In the first ascidian cell cycle, cytoplasmic and cortical reorganization is required for distributing maternal factors to their appropriate positions, resulting in the formation of the embryonic axis. This cytoplasmic reorganization is considered to depend on the cortical microfilament network in the first phase and on the sperm astral microtubule (MT) in the second phase. Recently, we described three novel MT structures: a deeply extended MT meshwork (DEM) in the entire subcortical region of the unfertilized egg, transiently accumulated MT fragments (TAF) in the vegetal pole, and a cortical MT array in the posterior vegetal cortex (CAMP). Particularly, our previous study showed CAMP to contribute to the movement of myoplasm. In addition, it is very similar to the parallel MT array, which appears during cortical rotation in Xenopus eggs. However, how these MT structures are organized is still unclear. Here, we investigated the relationship between the egg activation pathway and MT structures during the first ascidian cell cycle. First, we carefully analyzed cell cycle progression through meiosis I and II and the first mitosis, and successfully established a standard time table of cell cycle events. Using this time table as a reference, we precisely described the behavior of novel MT structures and revealed that it was closely correlated with cell cycle events. Moreover, pharmacological experiments supported the relationship between these MT structures and the signal transduction mechanisms that begin after fertilization, including Ca2+ signaling, MPF signaling, and MEK/MAPK signaling. Especially, CAMP formation was directed by activities of cyclin-dependent kinases. As these MT structures are conserved, at least, within chordate group, we emphasize the importance of understanding the controlling mechanisms of MT dynamics, which is important for embryonic axis determination in the ascidian egg.
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Affiliation(s)
- Toshiyuki Goto
- Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe, Hyogo 650-0047, Japan
| | - Kazumasa Kanda
- Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe, Hyogo 650-0047, Japan
| | - Takahito Nishikata
- Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe, Hyogo 650-0047, Japan.
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10
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Castro Colabianchi AM, Revinski DR, Encinas PI, Baez MV, Monti RJ, Rodríguez Abinal M, Kodjabachian L, Franchini LF, López SL. Notch1 is asymmetrically distributed from the beginning of embryogenesis and controls the ventral center. Development 2018; 145:dev.159368. [PMID: 29866901 DOI: 10.1242/dev.159368] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 05/25/2018] [Indexed: 12/14/2022]
Abstract
Based on functional evidence, we have previously demonstrated that early ventral Notch1 activity restricts dorsoanterior development in Xenopus We found that Notch1 has ventralizing properties and abolishes the dorsalizing activity of β-catenin by reducing its steady state levels, in a process that does not require β-catenin phosphorylation by glycogen synthase kinase 3β. In the present work, we demonstrate that Notch1 mRNA and protein are enriched in the ventral region from the beginning of embryogenesis in Xenopus This is the earliest sign of ventral development, preceding the localized expression of wnt8a, bmp4 and Ventx genes in the ventral center and the dorsal accumulation of nuclear β-catenin. Knockdown experiments indicate that Notch1 is necessary for the normal expression of genes essential for ventral-posterior development. These results indicate that during early embryogenesis ventrally located Notch1 promotes the development of the ventral center. Together with our previous evidence, these results suggest that ventral enrichment of Notch1 underlies the process by which Notch1 participates in restricting nuclear accumulation of β-catenin to the dorsal side.
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Affiliation(s)
- Aitana M Castro Colabianchi
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Biología Celular y Neurociencias 'Prof. E. De Robertis' (IBCN), Facultad de Medicina. Laboratorio de Embriología Molecular 'Prof. Dr. Andrés E. Carrasco', C1121ABG Buenos Aires, Argentina
| | - Diego R Revinski
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Biología Celular y Neurociencias 'Prof. E. De Robertis' (IBCN), Facultad de Medicina. Laboratorio de Embriología Molecular 'Prof. Dr. Andrés E. Carrasco', C1121ABG Buenos Aires, Argentina.,Aix Marseille Université, CNRS, IBDM, 13288 Marseille, France
| | - Paula I Encinas
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Biología Celular y Neurociencias 'Prof. E. De Robertis' (IBCN), Facultad de Medicina. Laboratorio de Embriología Molecular 'Prof. Dr. Andrés E. Carrasco', C1121ABG Buenos Aires, Argentina
| | - María Verónica Baez
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Biología Celular y Neurociencias 'Prof. E. De Robertis' (IBCN), Facultad de Medicina. Laboratorio de Embriología Molecular 'Prof. Dr. Andrés E. Carrasco', C1121ABG Buenos Aires, Argentina
| | - Renato J Monti
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Biología Celular y Neurociencias 'Prof. E. De Robertis' (IBCN), Facultad de Medicina. Laboratorio de Embriología Molecular 'Prof. Dr. Andrés E. Carrasco', C1121ABG Buenos Aires, Argentina
| | - Mateo Rodríguez Abinal
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Biología Celular y Neurociencias 'Prof. E. De Robertis' (IBCN), Facultad de Medicina. Laboratorio de Embriología Molecular 'Prof. Dr. Andrés E. Carrasco', C1121ABG Buenos Aires, Argentina
| | | | - Lucía F Franchini
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1428ADN Buenos Aires, Argentina
| | - Silvia L López
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Biología Celular y Neurociencias 'Prof. E. De Robertis' (IBCN), Facultad de Medicina. Laboratorio de Embriología Molecular 'Prof. Dr. Andrés E. Carrasco', C1121ABG Buenos Aires, Argentina
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11
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Favarolo MB, López SL. Notch signaling in the division of germ layers in bilaterian embryos. Mech Dev 2018; 154:122-144. [PMID: 29940277 DOI: 10.1016/j.mod.2018.06.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/08/2018] [Accepted: 06/18/2018] [Indexed: 01/09/2023]
Abstract
Bilaterian embryos are triploblastic organisms which develop three complete germ layers (ectoderm, mesoderm, and endoderm). While the ectoderm develops mainly from the animal hemisphere, there is diversity in the location from where the endoderm and the mesoderm arise in relation to the animal-vegetal axis, ranging from endoderm being specified between the ectoderm and mesoderm in echinoderms, and the mesoderm being specified between the ectoderm and the endoderm in vertebrates. A common feature is that part of the mesoderm segregates from an ancient bipotential endomesodermal domain. The process of segregation is noisy during the initial steps but it is gradually refined. In this review, we discuss the role of the Notch pathway in the establishment and refinement of boundaries between germ layers in bilaterians, with special focus on its interaction with the Wnt/β-catenin pathway.
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Affiliation(s)
- María Belén Favarolo
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Biología Celular y Neurociencias "Prof. E. De Robertis" (IBCN), Facultad de Medicina, Laboratorio de Embriología Molecular "Prof. Dr. Andrés E. Carrasco", Buenos Aires, Argentina
| | - Silvia L López
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Biología Celular y Neurociencias "Prof. E. De Robertis" (IBCN), Facultad de Medicina, Laboratorio de Embriología Molecular "Prof. Dr. Andrés E. Carrasco", Buenos Aires, Argentina.
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12
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Alfred V, Vaccari T. Mechanisms of Non-canonical Signaling in Health and Disease: Diversity to Take Therapy up a Notch? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1066:187-204. [PMID: 30030827 DOI: 10.1007/978-3-319-89512-3_9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Non-canonical Notch signaling encompasses a wide range of cellular processes, diverging considerably from the established paradigm. It can dispense of ligand, proteolytic or nuclear activity. Non-canonical Notch signaling events have been studied mostly in the fruit fly Drosophila melanogaster, the organism in which Notch was identified first and a powerful model for understanding signaling outcomes. However, non-canonical events are ill-defined and their involvement in human physiology is not clear, hampering our understanding of diseases arising from Notch signaling alterations. At a time in which therapies based on specific targeting of Notch signaling are still an unfulfilled promise, detailed understanding of non-canonical Notch events might be key to devising more specific and less toxic pharmacologic options. Based on the blueprint of non-canonical signaling in Drosophila, here, we review and rationalize current evidence about non-canonical Notch signaling. Our effort might inform Notch biologists developing new research avenues and clinicians seeking future treatment of Notch-dependent diseases.
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Affiliation(s)
- Victor Alfred
- IFOM, Istituto FIRC di Oncologia Molecolare at IFOM-IEO Campus, Milan, Italy
| | - Thomas Vaccari
- IFOM, Istituto FIRC di Oncologia Molecolare at IFOM-IEO Campus, Milan, Italy.
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy.
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13
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Souilhol C, Perea-Gomez A, Camus A, Beck-Cormier S, Vandormael-Pournin S, Escande M, Collignon J, Cohen-Tannoudji M. NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo. Development 2016; 142:3649-60. [PMID: 26534985 DOI: 10.1242/dev.121145] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
NOTCH signalling is an evolutionarily conserved pathway involved in intercellular communication essential for cell fate choices during development. Although dispensable for early aspects of mouse development, canonical RBPJ-dependent NOTCH signalling has been shown to influence lineage commitment during embryonic stem cell (ESC) differentiation. NOTCH activation in ESCs promotes the acquisition of a neural fate, whereas its suppression favours their differentiation into cardiomyocytes. This suggests that NOTCH signalling is implicated in the acquisition of distinct embryonic fates at early stages of mammalian development. In order to investigate in vivo such a role for NOTCH signalling in shaping cell fate specification, we use genetic approaches to constitutively activate the NOTCH pathway in the mouse embryo. Early embryonic development, including the establishment of anterior-posterior polarity, is not perturbed by forced NOTCH activation. By contrast, widespread NOTCH activity in the epiblast triggers dramatic gastrulation defects. These are fully rescued in a RBPJ-deficient background. Epiblast-specific NOTCH activation induces acquisition of neurectoderm identity and disrupts the formation of specific mesodermal precursors including the derivatives of the anterior primitive streak, the mouse organiser. In addition, we show that forced NOTCH activation results in misregulation of NODAL signalling, a major determinant of early embryonic patterning. Our study reveals a previously unidentified role for canonical NOTCH signalling during mammalian gastrulation. It also exemplifies how in vivo studies can shed light on the mechanisms underlying cell fate specification during in vitro directed differentiation.
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Affiliation(s)
- Céline Souilhol
- Institut Pasteur, Unité de Génétique Fonctionnelle de la Souris, Département de Biologie du Développement et Cellules Souches, 25 rue du docteur Roux, Paris F-75015, France CNRS URA 2578, Paris F-75015, France
| | - Aitana Perea-Gomez
- Institut Jacques Monod, CNRS, UMR7592, Univ Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France
| | - Anne Camus
- Institut Jacques Monod, CNRS, UMR7592, Univ Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France
| | - Sarah Beck-Cormier
- Institut Pasteur, Unité de Génétique Fonctionnelle de la Souris, Département de Biologie du Développement et Cellules Souches, 25 rue du docteur Roux, Paris F-75015, France CNRS URA 2578, Paris F-75015, France
| | - Sandrine Vandormael-Pournin
- Institut Pasteur, Unité de Génétique Fonctionnelle de la Souris, Département de Biologie du Développement et Cellules Souches, 25 rue du docteur Roux, Paris F-75015, France CNRS URA 2578, Paris F-75015, France
| | - Marie Escande
- Institut Pasteur, Unité de Génétique Fonctionnelle de la Souris, Département de Biologie du Développement et Cellules Souches, 25 rue du docteur Roux, Paris F-75015, France CNRS URA 2578, Paris F-75015, France
| | - Jérôme Collignon
- Institut Jacques Monod, CNRS, UMR7592, Univ Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France
| | - Michel Cohen-Tannoudji
- Institut Pasteur, Unité de Génétique Fonctionnelle de la Souris, Département de Biologie du Développement et Cellules Souches, 25 rue du docteur Roux, Paris F-75015, France CNRS URA 2578, Paris F-75015, France
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14
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Borggrefe T, Lauth M, Zwijsen A, Huylebroeck D, Oswald F, Giaimo BD. The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFβ/BMP and hypoxia pathways. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2015; 1863:303-13. [PMID: 26592459 DOI: 10.1016/j.bbamcr.2015.11.020] [Citation(s) in RCA: 150] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 11/18/2015] [Accepted: 11/19/2015] [Indexed: 01/12/2023]
Abstract
Notch signaling is a highly conserved signal transduction pathway that regulates stem cell maintenance and differentiation in several organ systems. Upon activation, the Notch receptor is proteolytically processed, its intracellular domain (NICD) translocates into the nucleus and activates expression of target genes. Output, strength and duration of the signal are tightly regulated by post-translational modifications. Here we review the intracellular post-translational regulation of Notch that fine-tunes the outcome of the Notch response. We also describe how crosstalk with other conserved signaling pathways like the Wnt, Hedgehog, hypoxia and TGFβ/BMP pathways can affect Notch signaling output. This regulation can happen by regulation of ligand, receptor or transcription factor expression, regulation of protein stability of intracellular key components, usage of the same cofactors or coregulation of the same key target genes. Since carcinogenesis is often dependent on at least two of these pathways, a better understanding of their molecular crosstalk is pivotal.
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Affiliation(s)
| | - Matthias Lauth
- Institute of Molecular Biology and Tumor Research, Philipps University Marburg, Germany
| | - An Zwijsen
- VIB Center for the Biology of Disease and Department of Human Genetics, KU Leuven, Leuven, Belgium
| | - Danny Huylebroeck
- Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Franz Oswald
- University Medical Center Ulm, Department of Internal Medicine I, Ulm, Germany
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15
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Żak M, Klis SFL, Grolman W. The Wnt and Notch signalling pathways in the developing cochlea: Formation of hair cells and induction of regenerative potential. Int J Dev Neurosci 2015; 47:247-58. [PMID: 26471908 DOI: 10.1016/j.ijdevneu.2015.09.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 09/25/2015] [Accepted: 09/26/2015] [Indexed: 12/21/2022] Open
Abstract
The Wnt and Notch signalling pathways control proliferation, specification, and cell fate choices during embryonic development and in adult life. Hence, there is much interest in both signalling pathways in the context of stem cell biology and tissue regeneration. In the developing ear, the Wnt and Notch signalling pathways specify otic cells and refine the ventral boundary of the otic placode. Since both signalling pathways control events essential for the formation of sensory cells, such as proliferation and hair cell differentiation, these pathways could hold promise for the regeneration of hair cells in adult mammalian cochlea. Indeed, modulating either the Wnt or Notch pathways can trigger the regenerative potential of supporting cells. In the neonatal mouse cochlea, Notch-mediated regeneration of hair cells partially depends on Wnt signalling, which implies an interaction between the pathways. This review presents how the Wnt and Notch signalling pathways regulate the formation of sensory hair cells and how modulating their activity induces regenerative potential in the mammalian cochlea.
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Affiliation(s)
- Magdalena Żak
- Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Room G.02.531, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.
| | - Sjaak F L Klis
- Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Room G.02.531, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Wilko Grolman
- Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Room G.02.531, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
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16
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Molecular signalling in hepatocellular carcinoma: Role of and crosstalk among WNT/ß-catenin, Sonic Hedgehog, Notch and Dickkopf-1. Can J Gastroenterol Hepatol 2015; 29:209-17. [PMID: 25965442 PMCID: PMC4444031 DOI: 10.1155/2015/172356] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma is the sixth most common cancer worldwide. In the majority of cases, there is evidence of existing chronic liver disease from a variety of causes including viral hepatitis B and C, alcoholic liver disease and nonalcoholic steatohepatitis. Identification of the signalling pathways used by hepatocellular carcinoma cells to proliferate, invade or metastasize is of paramount importance in the discovery and implementation of successfully targeted therapies. Activation of Wnt/β-catenin, Notch and Hedgehog pathways play a critical role in regulating liver cell proliferation during development and in controlling crucial functions of the adult liver in the initiation and progression of human cancers. β-catenin was identified as a protein interacting with the cell adhesion molecule E-cadherin at the cell-cell junction, and has been shown to be one of the most important mediators of the Wnt signalling pathway in tumourigenesis. Investigations into the role of Dikkopf-1 in hepatocellular carcinoma have demonstrated controversial results, with a decreased expression of Dickkopf-1 and soluble frizzled-related protein in various cancers on one hand, and as a possible negative prognostic indicator of hepatocellular carcinoma on the other. In the present review, the authors focus on the Wnt⁄β-catenin, Notch and Sonic Hedgehog pathways, and their interaction with Dikkopf-1 in hepatocellular carcinoma.
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17
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18
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FoxA4 favours notochord formation by inhibiting contiguous mesodermal fates and restricts anterior neural development in Xenopus embryos. PLoS One 2014; 9:e110559. [PMID: 25343614 PMCID: PMC4208771 DOI: 10.1371/journal.pone.0110559] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 09/24/2014] [Indexed: 11/19/2022] Open
Abstract
In vertebrates, the embryonic dorsal midline is a crucial signalling centre that patterns the surrounding tissues during development. Members of the FoxA subfamily of transcription factors are expressed in the structures that compose this centre. Foxa2 is essential for dorsal midline development in mammals, since knock-out mouse embryos lack a definitive node, notochord and floor plate. The related gene foxA4 is only present in amphibians. Expression begins in the blastula -chordin and -noggin expressing centre (BCNE) and is later restricted to the dorsal midline derivatives of the Spemann's organiser. It was suggested that the early functions of mammalian foxa2 are carried out by foxA4 in frogs, but functional experiments were needed to test this hypothesis. Here, we show that some important dorsal midline functions of mammalian foxa2 are exerted by foxA4 in Xenopus. We provide new evidence that the latter prevents the respecification of dorsal midline precursors towards contiguous fates, inhibiting prechordal and paraxial mesoderm development in favour of the notochord. In addition, we show that foxA4 is required for the correct regionalisation and maintenance of the central nervous system. FoxA4 participates in constraining the prospective rostral forebrain territory during neural specification and is necessary for the correct segregation of the most anterior ectodermal derivatives, such as the cement gland and the pituitary anlagen. Moreover, the early expression of foxA4 in the BCNE (which contains precursors of the whole forebrain and most of the midbrain and hindbrain) is directly required to restrict anterior neural development.
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19
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Collu GM, Hidalgo-Sastre A, Brennan K. Wnt-Notch signalling crosstalk in development and disease. Cell Mol Life Sci 2014; 71:3553-67. [PMID: 24942883 PMCID: PMC11113451 DOI: 10.1007/s00018-014-1644-x] [Citation(s) in RCA: 149] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 04/17/2014] [Accepted: 05/05/2014] [Indexed: 10/25/2022]
Abstract
The Notch and Wnt pathways are two of only a handful of highly conserved signalling pathways that control cell-fate decisions during animal development (Pires-daSilva and Sommer in Nat Rev Genet 4: 39-49, 2003). These two pathways are required together to regulate many aspects of metazoan development, ranging from germ layer patterning in sea urchins (Peter and Davidson in Nature 474: 635-639, 2011) to the formation and patterning of the fly wing (Axelrod et al in Science 271:1826-1832, 1996; Micchelli et al in Development 124:1485-1495, 1997; Rulifson et al in Nature 384:72-74, 1996), the spacing of the ciliated cells in the epidermis of frog embryos (Collu et al in Development 139:4405-4415, 2012) and the maintenance and turnover of the skin, gut lining and mammary gland in mammals (Clayton et al in Nature 446:185-189, 2007; Clevers in Cell 154:274-284, 2013; Doupe et al in Dev Cell 18:317-323, 2010; Lim et al in Science 342:1226-1230, 2013; Lowell et al in Curr Biol 10:491-500, 2000; van et al in Nature 435:959-963, 2005; Yin et al in Nat Methods 11:106-112, 2013). In addition, many diseases, including several cancers, are caused by aberrant signalling through the two pathways (Bolós et al in Endocr Rev 28: 339-363, 2007; Clevers in Cell 127: 469-480, 2006). In this review, we will outline the two signalling pathways, describe the different points of interaction between them, and cover how these interactions influence development and disease.
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Affiliation(s)
- Giovanna M Collu
- Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK,
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20
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Baumgartner BK, Cash G, Hansen H, Ostler S, Murtaugh LC. Distinct requirements for beta-catenin in pancreatic epithelial growth and patterning. Dev Biol 2014; 391:89-98. [PMID: 24721715 DOI: 10.1016/j.ydbio.2014.03.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2013] [Revised: 03/26/2014] [Accepted: 03/27/2014] [Indexed: 10/25/2022]
Abstract
Pancreatic exocrine and endocrine lineages arise from multipotent pancreatic progenitor cells (MPCs). Exploiting the mechanisms that govern expansion and differentiation of these cells could enhance efforts to generate β-cells from stem cells. Although our prior work indicates that the canonical Wnt signaling component β-catenin is required qualitatively for exocrine acinar but not endocrine development, precisely how this requirement plays out at the level of MPCs and their lineage-restricted progeny is unknown. In addition, the contribution of β-catenin function to β-cell development remains controversial. To resolve the potential roles of β-catenin in development of MPCs and β-cells, we generated pancreas- and pre-endocrine-specific β-catenin knockout mice. Pancreas-specific loss of β-catenin produced not only a dramatic reduction in acinar cell numbers, but also a significant reduction in β-cell mass. The loss of β-cells is due not to a defect in the differentiation of endocrine precursors, but instead correlates with an early and specific loss of MPCs. In turn, this reflects a novel role for β-catenin in maintaining proximal-distal patterning of the early epithelium, such that distal MPCs resort to a proximal, endocrine-competent "trunk" fate when β-catenin is deleted. Moreover, β-catenin maintains proximal-distal patterning, in part, by inhibiting Notch signaling. Subsequently, β-catenin is required for proliferation of both distal and proximal cells, driving overall organ growth. In distinguishing two distinct roles for β-catenin along the route of β-cell development, we suggest that temporally appropriate positive and negative manipulation of this molecule could enhance expansion and differentiation of stem cell-derived MPCs.
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Affiliation(s)
- Brett K Baumgartner
- University of Utah, Department of Human Genetics, 15 N. 2030 E. Rm 2100, Salt Lake City, UT 84112, USA
| | - Gabriela Cash
- University of Utah, Department of Human Genetics, 15 N. 2030 E. Rm 2100, Salt Lake City, UT 84112, USA
| | - Hillary Hansen
- University of Utah, Department of Human Genetics, 15 N. 2030 E. Rm 2100, Salt Lake City, UT 84112, USA
| | - Shawn Ostler
- University of Utah, Department of Human Genetics, 15 N. 2030 E. Rm 2100, Salt Lake City, UT 84112, USA
| | - L Charles Murtaugh
- University of Utah, Department of Human Genetics, 15 N. 2030 E. Rm 2100, Salt Lake City, UT 84112, USA.
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21
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Andersen P, Uosaki H, Shenje LT, Kwon C. Non-canonical Notch signaling: emerging role and mechanism. Trends Cell Biol 2012; 22:257-65. [PMID: 22397947 DOI: 10.1016/j.tcb.2012.02.003] [Citation(s) in RCA: 167] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Revised: 01/27/2012] [Accepted: 02/09/2012] [Indexed: 02/08/2023]
Abstract
Notch is an ancient transmembrane receptor with crucial roles in cell-fate choices. Although the 'canonical' Notch pathway and its core members are well established - involving ligand-induced cleavage of Notch for transcriptional regulation - it has been unclear whether Notch can also function independently of ligand and transcription ('non-canonically') through a common mechanism. Recent studies suggest that Notch can non-canonically exert its biological functions by post-translationally targeting Wnt/β-catenin signaling, an important cellular and developmental regulator. The non-canonical Notch pathway appears to be highly conserved from flies to mammals. Here, we discuss the emerging conserved mechanism and role of ligand/transcription-independent Notch signaling in cell and developmental biology.
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Affiliation(s)
- Peter Andersen
- Division of Cardiology, Department of Medicine, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USA
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Muñoz Descalzo S, Martinez Arias A. The structure of Wntch signalling and the resolution of transition states in development. Semin Cell Dev Biol 2012; 23:443-9. [PMID: 22326376 DOI: 10.1016/j.semcdb.2012.01.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 01/14/2012] [Accepted: 01/19/2012] [Indexed: 12/15/2022]
Abstract
During development, the emergence of different cell fates and their patterning into tissues and organs requires spatio-temporal coordination that controls the relative number of different cell types. Genetic analyses in different systems have revealed that interactions between Wnt and Notch signalling play pervasive roles in these processes. While many of these interactions can be explained in terms of transcriptional cross-talk between the effectors of these pathways, some of them require a different explanation. Experiments in Drosophila, Xenopus and mouse have revealed that Notch plays an important role in the modulation of the transcriptional activity of β-catenin (the main effector of Wnt signalling pathway, independently of its well characterized function as a membrane tethered transcription factor. These studies suggest that rather than two separate pathways, elements of Wnt and Notch signalling configure a single functional module, Wntch, that plays a key role in the resolution of cell fate decisions. Here we review the evidence for Wntch and present a current circuit view of the system, its control and its role in development with a special focus on stem cell populations.
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Muñoz-Descalzo S, de Navascues J, Arias AM. Wnt-Notch signalling: an integrated mechanism regulating transitions between cell states. Bioessays 2012; 34:110-8. [PMID: 22215536 DOI: 10.1002/bies.201100102] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Revised: 11/08/2011] [Accepted: 11/08/2011] [Indexed: 11/12/2022]
Abstract
The activity of Wnt and Notch signalling is central to many cell fate decisions during development and to the maintenance and differentiation of stem cell populations in homeostasis. While classical views refer to these pathways as independent signal transduction devices that co-operate in different systems, recent work has revealed intricate connections between their components. These observations suggest that rather than operating as two separate pathways, elements of Wnt and Notch signalling configure an integrated molecular device whose main function is to regulate transitions between cell states in development and homeostasis. Here, we propose a general framework for the structure and function of the interactions between these signalling systems that is focused on the notion of 'transition states', i.e. intermediates that arise during cell fate decision processes. These intermediates act as checkpoints in cell fate decision processes and are characterised by the mixed molecular identities of the states involved in these processes.
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