Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1)
- 14 May 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (23), 8965-8970
- https://doi.org/10.1073/pnas.1201652109
Abstract
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.Keywords
This publication has 30 references indexed in Scilit:
- Complex interplay between -catenin signalling and Notch effectors in intestinal tumorigenesisGut, 2011
- Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cellsProceedings of the National Academy of Sciences of the United States of America, 2010
- Paneth cells constitute the niche for Lgr5 stem cells in intestinal cryptsNature, 2010
- Atonal Homolog 1 Is Required for Growth and Differentiation Effects of Notch/γ-Secretase Inhibitors on Normal and Cancerous Intestinal Epithelial CellsGastroenterology, 2010
- Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell nicheNature Medicine, 2009
- Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal nicheNature, 2009
- Transcription Factor Achaete Scute-Like 2 Controls Intestinal Stem Cell FateCell, 2009
- Stem Cells, Self-Renewal, and Differentiation in the Intestinal EpitheliumAnnual Review of Physiology, 2009
- A genetic study of the role of the Wnt/β-catenin signalling in Paneth cell differentiationDevelopmental Biology, 2008
- Bmi1 is expressed in vivo in intestinal stem cellsNature Genetics, 2008