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Ascl2 acts as an R-spondin/Wnt-responsive switch to control stemness in intestinal crypts

Item Type:Article
Title:Ascl2 acts as an R-spondin/Wnt-responsive switch to control stemness in intestinal crypts
Creators Name:Schuijers, J. and Junker, J.P. and Mokry, M. and Hatzis, P. and Koo, B.K. and Sasselli, V. and van der Flier, L.G. and Cuppen, E. and van Oudenaarden, A. and Clevers, H.
Abstract:The Wnt signaling pathway controls stem cell identity in the intestinal epithelium and in many other adult organs. The transcription factor Ascl2 (a Wnt target gene) is a master regulator of intestinal stem cell identity. It is unclear how the continuous Wnt gradient along the crypt axis is translated into discrete expression of Ascl2 and discrete specification of stem cells at crypt bottoms. We show that (1) Ascl2 is regulated in a direct autoactivatory loop, leading to a distinct on/off expression pattern, and (2) Wnt/R-spondin can activate this regulatory loop. This mechanism interprets the Wnt levels in the intestinal crypt and translates the continuous Wnt signal into a discrete Ascl2 "on" or "off" decision. In turn, Ascl2, together with {beta}-catenin/Tcf, activates the genes fundamental to the stem cell state. In this manner, Ascl2 forms a transcriptional switch that is both Wnt responsive and Wnt dependent to define stem cell identity.
Keywords:Basic Helix-Loop-Helix Transcription Factors, Intestinal Mucosa, Stem Cells, Thrombospondins, Wnt Signaling Pathway, Animals, Mice
Source:Cell Stem Cell
Publisher:Cell Press / Elsevier
Page Range:158-170
Date:5 February 2015
Official Publication:https://doi.org/10.1016/j.stem.2014.12.006
PubMed:View item in PubMed

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