title: Notch receptor regulation of intestinal stem cell homeostasis and crypt regeneration.
abstract: The Notch signaling pathway regulates intestinal epithelial cell homeostasis, including stem cell maintenance, progenitor cell proliferation and differentiation. Notch1 and Notch2 receptors are expressed in the epithelium, but individual contributions to these functions are unclear. We used genetic deletion to define receptor roles on stem cell function, cell proliferation/differentiation, and repair after injury. Loss of Notch1 induced a transient secretory cell hyperplasia that spontaneously resolved over time. In contrast, deletion of Notch2 had no secretory cell effect. Compound deletions of Notch1 and Notch2 resulted in a more severe secretory cell hyperplasia than deletion of Notch1 alone. Furthermore, only double deletion of Notch1 and Notch2 decreased cell proliferation, suggesting a low threshold for maintenance of proliferation compared to differentiation. Stem cells were affected by deletion of Notch1, with reduced expression of Olfm4 and fewer LGR5(+) stem cells. Deletion of Notch2 had no apparent affect on stem cell homeostasis. However, we observed impaired crypt regeneration after radiation in both Notch1- and Notch2-deleted intestine, suggesting that higher Notch activity is required post-injury. These findings suggest that Notch1 is the primary receptor regulating intestinal stem cell function and that Notch1 and Notch2 together regulate epithelial cell proliferation, cell fate determination, and post-injury regeneration.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Alexis J
authors.initials: AJ
authors.lastname: Carulli
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Keeley
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Elise S
authors.initials: ES
authors.lastname: Demitrack
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jooho
authors.initials: J
authors.lastname: Chung
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address: lcsam@umich.edu.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Samuelson
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D003433:Crosses, Genetic; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D006706:Homeostasis; D006965:Hyperplasia / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D051881:Receptor, Notch1 / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2
keywords: Cell fate determination; Irradiation injury; Notch signaling; Notch1, Notch2, crypt base columnar stem cell; Olfm4, Lgr5, goblet cell hyperplasia
references.citation: Am J Anat. 1969 Dec;126(4):507-25
references.pmid: 5369113
references.citation: Genesis. 2004 Jul;39(3):186-93
references.pmid: 15282745
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: Dev Dyn. 2005 Aug;233(4):1332-6
references.pmid: 15937933
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12443-8
references.pmid: 16107537
references.citation: Genesis. 2006 Jan;44(1):29-33
references.pmid: 16397869
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G970-9
references.pmid: 16399875
references.citation: Development. 2007 Feb;134(3):535-44
references.pmid: 17215306
references.citation: Gastroenterology. 2007 Jun;132(7):2478-88
references.pmid: 17570220
references.citation: Nature. 2007 Oct 25;449(7165):1003-7
references.pmid: 17934449
references.citation: EMBO Rep. 2008 Apr;9(4):377-83
references.pmid: 18274550
references.citation: Cell. 2009 Mar 6;136(5):903-12
references.pmid: 19269367
references.citation: Am J Physiol Gastrointest Liver Physiol. 2014 Mar 1;306(5):G404-11
references.pmid: 24368703
references.citation: Nature. 2009 May 14;459(7244):262-5
references.pmid: 19329995
references.citation: Gastroenterology. 2009 Oct;137(4):1333-45.e1-3
references.pmid: 19549527
references.citation: Exp Cell Res. 2010 Feb 1;316(3):452-65
references.pmid: 19786015
references.citation: Nature. 2010 Apr 15;464(7291):1052-7
references.pmid: 20393564
references.citation: Dev Biol. 2010 Oct 15;346(2):215-23
references.pmid: 20691176
references.citation: Cell. 2010 Oct 1;143(1):134-44
references.pmid: 20887898
references.citation: Nature. 2011 Jan 20;469(7330):415-8
references.pmid: 21113151
references.citation: Gastroenterology. 2011 Apr;140(4):1230-1240.e1-7
references.pmid: 21238454
references.citation: J Biol Chem. 2011 Apr 1;286(13):11427-33
references.pmid: 21282114
references.citation: PLoS One. 2011;6(10):e25785
references.pmid: 21991352
references.citation: Development. 2012 Feb;139(3):488-97
references.pmid: 22190634
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):466-71
references.pmid: 22190486
references.citation: Am J Physiol Gastrointest Liver Physiol. 2012 May 15;302(10):G1111-32
references.pmid: 22361729
references.citation: EMBO J. 2012 Jul 18;31(14):3079-91
references.pmid: 22692129
references.citation: J Clin Invest. 2013 Apr;123(4):1590-604
references.pmid: 23454750
references.citation: Nat Genet. 2000 Jan;24(1):36-44
references.pmid: 10615124
references.citation: Science. 2001 Dec 7;294(5549):2155-8
references.pmid: 11739954
references.citation: Nat Immunol. 2002 May;3(5):443-50
references.pmid: 11967543
references.citation: Gene Expr Patterns. 2002 Dec;2(3-4):247-50
references.pmid: 12617809
references.citation: J Histochem Cytochem. 2004 Apr;52(4):509-16
references.pmid: 15034002
references.citation: Dev Biol. 2004 May 1;269(1):81-94
references.pmid: 15081359
references.citation: Cell Prolif. 1992 Nov;25(6):559-78
references.pmid: 1457605