title: Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis.
abstract: Proper organ homeostasis requires tight control of adult stem cells and differentiation through the integration of multiple inputs. In the mouse small intestine, Notch and Wnt signaling are required both for stem cell maintenance and for a proper balance of differentiation between secretory and absorptive cell lineages. In the absence of Notch signaling, stem cells preferentially generate secretory cells at the expense of absorptive cells. Here, we use function-blocking antibodies against Notch receptors to demonstrate that Notch blockade perturbs intestinal stem cell function by causing a derepression of the Wnt signaling pathway, leading to misexpression of prosecretory genes. Importantly, attenuation of the Wnt pathway rescued the phenotype associated with Notch blockade. These studies bring to light a negative regulatory mechanism that maintains stem cell activity and balanced differentiation, and we propose that the interaction between Wnt and Notch signaling described here represents a common theme in adult stem cell biology.
authors.affiliation: Departments of Orofacial Sciences and Pediatrics, Institute of Human Genetics and Program in Craniofacial Biology, UCSF, 513 Parnassus Avenue, San Francisco, CA 94143-0442, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Biehs
authors.affiliation: Department of Antibody Engineering, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Chiu
authors.affiliation: Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Siebel
authors.affiliation: Department of Antibody Engineering, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Costa
authors.affiliation: Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: desauvage.fred@gene.com.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.affiliation: Departments of Orofacial Sciences and Pediatrics, Institute of Human Genetics and Program in Craniofacial Biology, UCSF, 513 Parnassus Avenue, San Francisco, CA 94143-0442, USA. Electronic address: ophir.klein@ucsf.edu.
authors.forename: Ophir D
authors.initials: OD
authors.lastname: Klein
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D051880:Receptors, Notch
references.citation: Gastroenterology. 2005 Aug;129(2):626-38
references.pmid: 16083717
references.citation: Gastroenterology. 2012 Dec;143(6):1518-1529.e7
references.pmid: 22922422
references.citation: Annu Rev Cell Dev Biol. 2006;22:339-73
references.pmid: 16824012
references.citation: Mol Cell Biol. 2007 Nov;27(21):7551-9
references.pmid: 17785439
references.citation: Nature. 2007 Oct 25;449(7165):1003-7
references.pmid: 17934449
references.citation: J Biol Chem. 2010 Jan 1;285(1):392-400
references.pmid: 19864427
references.citation: Nature. 2010 Apr 15;464(7291):1052-7
references.pmid: 20393564
references.citation: Gastroenterology. 2010 Sep;139(3):918-28, 928.e1-6
references.pmid: 20621629
references.citation: Dev Biol. 2010 Oct 15;346(2):215-23
references.pmid: 20691176
references.citation: Nature. 2011 Jan 20;469(7330):415-8
references.pmid: 21113151
references.citation: J Biol Chem. 2011 Apr 1;286(13):11427-33
references.pmid: 21282114
references.citation: Nature. 2011 Aug 18;476(7360):293-7
references.pmid: 21727895
references.citation: Nature. 2013 Mar 7;495(7439):65-9
references.pmid: 23446353
references.citation: Science. 2001 Dec 7;294(5549):2155-8
references.pmid: 11739954
references.citation: Nat Genet. 2003 Mar;33(3):416-21
references.pmid: 12590261
references.citation: Genes Dev. 2003 Jul 15;17(14):1709-13
references.pmid: 12865297
references.citation: Nat Genet. 1998 Aug;19(4):379-83
references.pmid: 9697701
references.citation: Development. 2005 Mar;132(6):1443-51
references.pmid: 15716339
references.citation: Nat Cell Biol. 2005 Apr;7(4):381-6
references.pmid: 15778706
references.citation: Nature. 2005 Jun 16;435(7044):959-63
references.pmid: 15959515
references.citation: Nature. 2005 Jun 16;435(7044):964-8
references.pmid: 15959516
references.citation: Cell Cycle. 2006 Jan;5(1):23-6
references.pmid: 16357527
references.citation: J Cell Biochem. 2012 Jan;113(1):31-8
references.pmid: 21866564
references.citation: Development. 2012 Feb;139(3):488-97
references.pmid: 22190634
references.citation: Mol Cell Biol. 2012 May;32(10):1918-27
references.pmid: 22393260
references.citation: PLoS One. 2012;7(7):e40976
references.pmid: 22815884
references.citation: Dev Dyn. 2005 Aug;233(4):1332-6
references.pmid: 15937933