| Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1). | |
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MedLine Citation:
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PMID: 22586121 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Intestinal epithelium has the capacity to self-renew and generate differentiated cells through the existence of two types of epithelial stem cells: active crypt base columnar cells (CBCs) and quiescent +4 cells. The behaviors of these cells are regulated both by intrinsic programs and by extrinsic signals sent by neighboring cells, which define the niche. It is clear that the β-catenin pathway acts as an essential intrinsic signal for the maintenance and proliferation of CBC, and it was recently proposed that Paneth cells provide a crucial niche by secreting Wingless/Int (Wnt) ligands. Here, we examined the effect of disrupting the intestinal stem cell niche by inducible deletion of the transcription factor Math1 (Atoh1), an essential driver of secretory cell differentiation. We found that complete loss of Paneth cells attributable to Math1 deficiency did not perturb the crypt architecture and allowed the maintenance and proliferation of CBCs. Indeed, Math1-deficient crypt cells tolerated in vivo Paneth cell loss and maintained active β-catenin signaling but could not grow ex vivo without exogenous Wnt, implying that, in vivo, underlying mucosal cells act as potential niche. Upon irradiation, Math1-deficient crypt cells regenerated and CBCs continued cycling. Finally, CBC stem cells deficient in adenomatous polyposis coli (Apc) and Math1 were able to promote intestinal tumorigenesis. We conclude that in vivo, Math1-deficient crypts counteract the absence of Paneth cell-derived Wnts and prevent CBC stem cell exhaustion. |
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Authors:
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Aurélie Durand; Bridgitte Donahue; Grégory Peignon; Franck Letourneur; Nicolas Cagnard; Christian Slomianny; Christine Perret; Noah F Shroyer; Béatrice Romagnolo |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-05-14 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 109 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-06-06 Completed Date: 2012-08-27 Revised Date: 2013-05-09 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 8965-70 Citation Subset: IM |
Affiliation:
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Institut Cochin, Department of Endocrinology, Metabolism and Cancer, Université Paris Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, 75014 Paris, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Basic Helix-Loop-Helix Transcription Factors / deficiency* Immunohistochemistry In Situ Hybridization Intestinal Mucosa / cytology* Mice Microarray Analysis Microscopy, Electron Paneth Cells / cytology* Polymerase Chain Reaction Signal Transduction / physiology* Stem Cells / ultrastructure* Wnt Proteins / deficiency beta Catenin / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA142826/CA/NCI NIH HHS; R01 CA142826/CA/NCI NIH HHS; R01 DK092306/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Atoh1 protein, mouse; 0/Basic Helix-Loop-Helix Transcription Factors; 0/Wnt Proteins; 0/beta Catenin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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