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.
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, CancerGenomiCs.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Jurian
authors.initials: J
authors.lastname: Schuijers
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, CancerGenomiCs.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Jan Philipp
authors.initials: JP
authors.lastname: Junker
authors.affiliation: Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands.
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
authors.affiliation: Biomedical Sciences Research Center "Alexander Fleming," 16672 Vari, Greece.
authors.forename: Pantelis
authors.initials: P
authors.lastname: Hatzis
authors.affiliation: 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.
authors.forename: Bon-Kyoung
authors.initials: BK
authors.lastname: Koo
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, CancerGenomiCs.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sasselli
authors.affiliation: 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.
authors.forename: Laurens G
authors.initials: LG
authors.lastname: van der Flier
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, CancerGenomiCs.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, CancerGenomiCs.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
authors.affiliation: 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.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019699:Thrombospondins; C489311:Ascl2 protein, mouse; C518903:RSPO1 protein, mouse