Ascl2 Acts as an R-spondin/Wnt-Responsive Switch to Control Stemness in Intestinal Crypts

• Published in: Cell stem cell Vol. 16; no. 2; pp. 158 - 170
• Main Authors: Schuijers, Jurian, Junker, Jan Philipp, Mokry, Michal, Hatzis, Pantelis, Koo, Bon-Kyoung, Sasselli, Valentina, van der Flier, Laurens G., Cuppen, Edwin, van Oudenaarden, Alexander, Clevers, Hans
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.02.2015
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Intestinal Mucosa - cytology; Intestinal Mucosa - metabolism; Mice; Stem Cells - cytology; Stem Cells - metabolism; Thrombospondins - genetics; Thrombospondins - metabolism; Wnt Signaling Pathway
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2014.12.006

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. [Display omitted] •Wnt and Ascl2 activate a gene signature fundamental to the intestinal stem cell state•β-catenin/Tcf4 and Ascl2 co-occupy DNA and synergistically activate transcription•Ascl2 forms an autoactivating loop that leads to an on/off expression pattern•This loop translates the Wnt gradient into a discrete transcriptional decision The Wnt signaling pathway controls stem cell identity in the intestinal epithelium, but it has remained unclear how the continuous Wnt gradient is translated into discrete cell type specification. Schuijers et al. show that the transcription factor Ascl2 forms a bimodal switch that interprets Wnt levels and specifies stem cells.