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

Jurian Schuijers; Jan Philipp Junker; Michal Mokry; Pantelis Hatzis; Bon Kyoung Koo; Valentina Sasselli; Laurens G. Van Der Flier; Edwin Cuppen; Alexander Van Oudenaarden; Hans Clevers

doi:10.1016/j.stem.2014.12.006

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

Jurian Schuijers, Jan Philipp Junker, Michal Mokry, Pantelis Hatzis, Bon Kyoung Koo, Valentina Sasselli, Laurens G. Van Der Flier, Edwin Cuppen, Alexander Van Oudenaarden, Hans Clevers

Research output: Contribution to journal › Article › peer-review

195 Citations (Scopus)

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 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.

Original language	English
Pages (from-to)	158-170
Number of pages	13
Journal	Cell Stem Cell
Volume	16
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2014.12.006
Publication status	Published - 5 Feb 2015
Externally published	Yes

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title = "Ascl2 acts as an R-spondin/wnt-responsive switch to control stemness in intestinal crypts",

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 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.",

author = "Jurian Schuijers and Junker, {Jan Philipp} and Michal Mokry and Pantelis Hatzis and Koo, {Bon Kyoung} and Valentina Sasselli and {Van Der Flier}, {Laurens G.} and Edwin Cuppen and {Van Oudenaarden}, Alexander and Hans Clevers",

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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

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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.

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

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