title: Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice.
abstract: OBJECTIVE
  We investigated the role of bone morphogenetic protein (BMP) signaling in the regulation of gastric epithelial cell growth and differentiation by generating transgenic mice that express the BMP inhibitor noggin in the stomach.
  
  
  METHODS
  The promoter of the mouse H+/K+-ATPase β-subunit gene, which is specifically expressed in parietal cells, was used to regulate expression of noggin in the gastric epithelium of mice. The transgenic mice were analyzed for noggin expression, tissue morphology, cellular composition of the gastric mucosa, gastric acid content, and plasma levels of gastrin. Tissues were analyzed by immunohistochemical, quantitative real-time polymerase chain reaction, immunoblot, microtitration, and radioimmunoassay analyses.
  
  
  RESULTS
  In the stomachs of the transgenic mice, phosphorylation of Smad 1, 5, and 8 decreased, indicating inhibition of BMP signaling. Mucosa were of increased height, with dilated glands, cystic structures, reduced numbers of parietal cells, and increased numbers of cells that coexpressed intrinsic factor, trefoil factor 2, and Griffonia (Bandeiraea) simplicifolia lectin II, compared with wild-type mice. In the transgenic mice, levels of the H+/K+-ATPase α-subunit protein and messenger RNA were reduced, whereas those of intrinsic factor increased. The transgenic mice were hypochloridric and had an increased number of Ki67- and proliferating cell nuclear antigen-positive cells; increased levels of plasma gastrin; increased expression of transforming growth factor-α, amphiregulin, and gastrin; and activation of extracellular signal-regulated kinase 2.
  
  
  CONCLUSIONS
  Inhibiting BMP signaling in the stomachs of mice by expression of noggin causes loss of parietal cells, development of transitional cells that express markers of mucus neck and zymogenic lineages, and activation of proliferation. BMPs are therefore important regulators of gastric epithelial cell homeostasis.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Shinohara
authors.forename: Maria
authors.initials: M
authors.lastname: Mao
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Keeley
authors.forename: Mohamad
authors.initials: M
authors.lastname: El-Zaatari
authors.forename: Hyuk-Joon
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Eaton
authors.forename: Linda C
authors.initials: LC
authors.lastname: Samuelson
authors.forename: Juanita L
authors.initials: JL
authors.lastname: Merchant
authors.forename: James R
authors.initials: JR
authors.lastname: Goldenring
authors.forename: Andrea
authors.initials: A
authors.lastname: Todisco
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D019872:Chief Cells, Gastric / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D007437:Intrinsic Factor / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009077:Mucins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D010295:Parietal Cells, Gastric / Q000166:cytology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D037121:Plant Lectins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013270:Stomach / Q000166:cytology*; D000071164:Trefoil Factor-2; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D007437:Intrinsic Factor; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D037121:Plant Lectins; D000071164:Trefoil Factor-2; D000099176:Noggin Protein; C045475:Griffonia simplicifolia lectins; C481546:TFF2 protein, mouse
references.citation: J Gastroenterol. 2006 Nov;41(11):1064-75
references.pmid: 17160517
references.citation: Lab Invest. 2005 May;85(5):702-15
references.pmid: 15765119
references.citation: Am J Hum Genet. 2001 Oct;69(4):704-11
references.pmid: 11536076
references.citation: Cancer Res. 2009 Apr 1;69(7):2729-33
references.pmid: 19318548
references.citation: Cancer Res. 1999 Dec 15;59(24):6113-7
references.pmid: 10626800
references.citation: Gastroenterology. 2004 Aug;127(2):582-94
references.pmid: 15300590
references.citation: J Physiol. 1999 Jul 15;518 ( Pt 2):315-24
references.pmid: 10381581
references.citation: Am J Physiol. 1993 Feb;264(2 Pt 1):G390-6
references.pmid: 8447422
references.citation: Science. 2004 Mar 12;303(5664):1684-6
references.pmid: 15017003
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G970-9
references.pmid: 16399875
references.citation: Science. 1998 May 29;280(5368):1455-7
references.pmid: 9603738
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Nov;291(5):G762-5
references.pmid: 17030897
references.citation: J Biol Chem. 1996 Feb 16;271(7):3671-6
references.pmid: 8631979
references.citation: Development. 2007 Jan;134(1):211-22
references.pmid: 17164426
references.citation: Cell. 1996 Aug 23;86(4):599-606
references.pmid: 8752214
references.citation: Biochem Biophys Res Commun. 2004 Mar 26;316(1):100-6
references.pmid: 15003517
references.citation: J Med Genet. 2004 Jul;41(7):484-91
references.pmid: 15235019
references.citation: Genes Dev. 2005 Dec 1;19(23):2783-810
references.pmid: 16322555
references.citation: Oncogene. 2006 Apr 27;25(18):2666-73
references.pmid: 16314833
references.citation: J Biol Chem. 2005 Apr 22;280(16):15700-8
references.pmid: 15691835
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Dec;291(6):G999-1004
references.pmid: 17090722
references.citation: Peptides. 1999;20(7):885-98
references.pmid: 10477091
references.citation: Cytokine Growth Factor Rev. 1998 Mar;9(1):49-61
references.pmid: 9720756
references.citation: Physiol Rev. 2007 Oct;87(4):1343-75
references.pmid: 17928586
references.citation: J Clin Invest. 2002 Jan;109(2):193-204
references.pmid: 11805131
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Sep;293(3):G607-14
references.pmid: 17600042
references.citation: Dev Biol. 1997 Aug 15;188(2):235-47
references.pmid: 9268572
references.citation: Genes Dev. 1995 Sep 1;9(17):2105-16
references.pmid: 7657163
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Jan;282(1):G175-83
references.pmid: 11751171
references.citation: N Engl J Med. 2000 Dec 7;343(23):1697-701
references.pmid: 11106719
references.citation: Gastroenterology. 2001 Aug;121(2):317-28
references.pmid: 11487541
references.citation: Gastroenterology. 2000 Jun;118(6):1080-93
references.pmid: 10833483
references.citation: Development. 2005 Jan;132(2):279-89
references.pmid: 15590741
references.citation: Am J Physiol Gastrointest Liver Physiol. 2005 Feb;288(2):G362-75
references.pmid: 15647607
references.citation: J Biol Chem. 1995 Jun 30;270(26):15777-88
references.pmid: 7797580
references.citation: Cell. 2000 Jan 21;100(2):189-92
references.pmid: 10660041
references.citation: J Clin Invest. 1989 Sep;84(3):1017-23
references.pmid: 2760208
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2431-5
references.pmid: 8637891
references.citation: J Biol Chem. 1998 Dec 11;273(50):33533-9
references.pmid: 9837934
references.citation: J Clin Invest. 2008 Jul;118(7):2459-70
references.pmid: 18535670
references.citation: Physiol Genomics. 2006 Jan 12;24(2):124-32
references.pmid: 16278279
references.citation: Cancer. 1995 Mar 15;75(6 Suppl):1460-6
references.pmid: 7889475
references.citation: Gastroenterology. 1992 Dec;103(6):1950-63
references.pmid: 1451986
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Jul;291(1):G135-45
references.pmid: 16769811
references.citation: Cancer Res. 2007 Sep 1;67(17):8149-55
references.pmid: 17804727
references.citation: Gastroenterology. 2007 Sep;133(3):887-96
references.pmid: 17678919