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Cell Stem Cell. 2015 Feb 5;16(2):158-70. doi: 10.1016/j.stem.2014.12.006. Epub 2015 Jan 22.

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

Author information

1
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, CancerGenomiCs.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
2
Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands.
3
Biomedical Sciences Research Center "Alexander Fleming," 16672 Vari, Greece.
4
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, CancerGenomiCs.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands; Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
5
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, CancerGenomiCs.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands; SomantiX B.V., Utrecht, Padualaan 8, 3584 CH Utrecht, the Netherlands.
6
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, CancerGenomiCs.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. Electronic address: h.clevers@hubrecht.eu.

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.

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PMID:
25620640
DOI:
10.1016/j.stem.2014.12.006
[Indexed for MEDLINE]
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