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

TY - JOUR

T1 - Ascl2 acts as an R-spondin/Wnt-responsive switch to control stemness in intestinal crypts

AU - Schuijers, Jurian

AU - Junker, Jan Philipp

AU - Mokry, Michal

AU - Hatzis, Pantelis

AU - Koo, Bon-Kyoung

AU - Sasselli, Valentina

AU - van der Flier, Laurens G

AU - Cuppen, Edwin

AU - van Oudenaarden, Alexander

AU - Clevers, Hans

N1 - Copyright © 2015 Elsevier Inc. All rights reserved.

PY - 2015/2/5

Y1 - 2015/2/5

N2 - 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 β-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.

AB - 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 β-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.

U2 - 10.1016/j.stem.2014.12.006

DO - 10.1016/j.stem.2014.12.006

M3 - Article

C2 - 25620640

SN - 1934-5909

VL - 16

SP - 158

EP - 170

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -