title: Lgr4 gene deficiency increases susceptibility and severity of dextran sodium sulfate-induced inflammatory bowel disease in mice.
abstract: Lgr4/Gpr48 is one of the newly identified R-spondins receptors and potentiates Wnt signaling, which regulates intestinal homeostasis. We used a hypomorphic mouse strain to determine the role of Lgr4 in intestinal inflammation and recovery. Intestinal inflammation was induced with dextran sulfate sodium (DSS) followed by a recovery period. Intestinal inflammation symptoms and molecular mechanisms were examined. We found that Lgr4(-/-) mice exhibited dramatically higher susceptibility to and mortality from DSS-induced inflammatory bowel disease than WT mice. Lgr4 deficiency resulted in greatly reduced numbers of either Paneth cells or stem cells in the intestine. During the intestinal regeneration process, cell proliferation but not apoptosis of intestinal epithelial cells was significantly impaired in Lgr4(-/-) mice. When Wnt/β-catenin signaling was reactivated by crossing with APC(min)(/+) mice or by treating with a GSK-3β inhibitor, the number of Paneth cells was partially restored and the mortality caused by DSS-induced inflammatory bowel disease was strikingly reduced in Lgr4-deficient animals. Thus, Lgr4 is critically involved in the maintenance of intestinal homeostasis and protection against inflammatory bowel disease through modulation of the Wnt/β-catenin signaling pathway.
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors: Shijie
authors: S
authors: Liu
authors: Yu
authors: Y
authors: Qian
authors: Liang
authors: L
authors: Li
authors: Gaigai
authors: G
authors: Wei
authors: Yuting
authors: Y
authors: Guan
authors: Hongjie
authors: H
authors: Pan
authors: Xin
authors: X
authors: Guan
authors: Long
authors: L
authors: Zhang
authors: Xiaoling
authors: X
authors: Lu
authors: Yongxiang
authors: Y
authors: Zhao
authors: Mingyao
authors: M
authors: Liu
authors: Dali
authors: D
authors: Li
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D003092:Colitis / Q000235:genetics / Q000378:metabolism*; D003911:Dextrans / Q000494:pharmacology*; D055808:Drug Discovery; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006706:Homeostasis; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013431:Sulfates / Q000494:pharmacology*; D019699:Thrombospondins / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D003911:Dextrans; C496200:LGR4 protein, mouse; C518903:RSPO1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D013431:Sulfates; D019699:Thrombospondins; D051153:Wnt Proteins; D051176:beta Catenin; C012036:sodium sulfate
references: Nature. 2008 Nov 13;456(7219):259-63
references: 18849966
references: Nature. 2011 Jun 15;474(7351):318-26
references: 21677748
references: J Biol Chem. 1997 Sep 19;272(38):23729-40
references: 9295317
references: Dev Cell. 2010 Aug 17;19(2):259-69
references: 20708588
references: Proc Natl Acad Sci U S A. 2008 Apr 22;105(16):6081-6
references: 18424556
references: Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10272-7
references: 21652773
references: Nat Genet. 1998 Aug;19(4):379-83
references: 9697701
references: Annu Rev Immunol. 2010;28:573-621
references: 20192811
references: Cell. 2008 Sep 5;134(5):743-56
references: 18775308
references: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20858-63
references: 19075245
references: N Engl J Med. 2002 Aug 8;347(6):417-29
references: 12167685
references: Nature. 2011 Sep 18;478(7368):255-9
references: 21927002
references: Nature. 2011 Jun 15;474(7351):307-17
references: 21677747
references: Nature. 2011 Jun 15;474(7351):298-306
references: 21677746
references: PLoS One. 2009;4(2):e4496
references: 19221600
references: Development. 2009 Aug;136(16):2747-56
references: 19605502
references: J Gastroenterol. 2005 Jan;40(1):16-23
references: 15692785
references: Cell. 2009 Mar 6;136(5):903-12
references: 19269367
references: Nature. 2011 Jul 04;476(7360):293-7
references: 21727895
references: Cell. 2000 Jan 7;100(1):157-68
references: 10647940
references: Nature. 2012 Apr 29;485(7397):195-200
references: 22575959
references: Nature. 2011 Sep 14;477(7364):335-9
references: 21921917
references: Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11452-7
references: 21693646
references: Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):466-71
references: 22190486
references: EMBO Rep. 2011 Jun;12(6):558-64
references: 21508962
references: Genes Dev. 2008 Jul 15;22(14):1856-64
references: 18628392
references: Front Biosci. 2007 Jan 01;12:471-91
references: 17127311
references: Dev Biol. 2006 Feb 15;290(2):421-34
references: 16406039
references: Mol Endocrinol. 2000 Aug;14(8):1257-71
references: 10935549
references: Nat Genet. 2008 Jul;40(7):915-20
references: 18536716
references: Gastroenterology. 1997 Apr;112(4):1231-40
references: 9098007
references: J Biol Chem. 2008 Dec 26;283(52):36687-97
references: 18955481
references: Development. 2010 Jan;137(1):151-7
references: 20023170
references: Science. 2011 Dec 9;334(6061):1420-4
references: 22075725
references: Nature. 2007 Oct 25;449(7165):1003-7
references: 17934449
references: Nature. 2011 Jan 20;469(7330):415-8
references: 21113151
references: Mol Endocrinol. 2004 Sep;18(9):2241-54
references: 15192078
references: Gastroenterology. 2010 Sep;139(3):869-81, 881.e1-9
references: 20580720
references: EMBO Rep. 2011 Sep 30;12(10):1055-61
references: 21909076
references: Immunity. 2010 Mar 26;32(3):392-402
references: 20303298
references: Science. 2006 Aug 25;313(5790):1126-30
references: 16931762
references: Gastroenterology. 2011 Jul;141(1):259-68, 268.e1-8
references: 21440550
references: Gastroenterology. 1995 Oct;109(4):1344-67
references: 7557106