title: XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum.
abstract: OBJECTIVE
  The transition of gastric epithelial mucous neck cells (NCs) to digestive enzyme-secreting zymogenic cells (ZCs) involves an increase in rough endoplasmic reticulum (ER) and formation of many large secretory vesicles. The transcription factor MIST1 is required for granulogenesis of ZCs. The transcription factor XBP1 binds the Mist1 promoter and induces its expression in vitro and expands the ER in other cell types. We investigated whether XBP1 activates Mist1 to regulate ZC differentiation.
  
  
  METHODS
  Xbp1 was inducibly deleted in mice using a tamoxifen/Cre-loxP system; effects on ZC size and structure (ER and granule formation) and gastric differentiation were studied and quantified for up to 13 months after deletion using morphologic, immunofluorescence, quantitative reverse-transcriptase polymerase chain reaction, and immunoblot analyses. Interactions between XBP1 and the Mist1 promoter were studied by chromatin immunoprecipitation from mouse stomach and in XBP1-transfected gastric cell lines.
  
  
  RESULTS
  Tamoxifen-induced deletion of Xbp1 (Xbp1Δ) did not affect survival of ZCs but prevented formation of their structure. Xbp1Δ ZCs shrank 4-fold, compared with those of wild-type mice, with granulogenesis and cell shape abnormalities and disrupted rough ER. XBP1 was required and sufficient for transcriptional activation of MIST1. ZCs that developed in the absence of XBP1 induced ZC markers (intrinsic factor, pepsinogen C) but showed abnormal retention of progenitor NC markers.
  
  
  CONCLUSIONS
  XBP1 controls the transcriptional regulation of ZC structural development; it expands the lamellar rough ER and induces MIST1 expression to regulate formation of large granules. XBP1 is also required for loss of mucous NC markers as ZCs form.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Huh
authors.forename: Emel
authors.initials: E
authors.lastname: Esen
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Geahlen
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bredemeyer
authors.forename: Ann-Hwee
authors.initials: AH
authors.lastname: Lee
authors.forename: Guanglu
authors.initials: G
authors.lastname: Shi
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Jason C
authors.initials: JC
authors.lastname: Mills
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D019872:Chief Cells, Gastric / Q000166:cytology* / Q000502:physiology* / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018870:Endoplasmic Reticulum, Rough / Q000502:physiology*; D019426:Integrases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D011401:Promoter Regions, Genetic / Q000502:physiology; D000071701:Regulatory Factor X Transcription Factors; D022142:Secretory Vesicles / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D019426:Integrases; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C491312:Bhlha15 protein, mouse; C000605544:Xbp1 protein, mouse; C045073:Cre recombinase
references.citation: Development. 2007 Jan;134(1):211-22
references.pmid: 17164426
references.citation: Anat Rec. 1993 Jun;236(2):297-313
references.pmid: 8338234
references.citation: Mol Cell Biol. 2010 Mar;30(5):1269-84
references.pmid: 20038531
references.citation: Am J Physiol Gastrointest Liver Physiol. 2010 Aug;299(2):G368-80
references.pmid: 20413717
references.citation: Am J Physiol Gastrointest Liver Physiol. 2005 Feb;288(2):G362-75
references.pmid: 15647607
references.citation: EMBO J. 2005 Dec 21;24(24):4368-80
references.pmid: 16362047
references.citation: Genes Cells. 2008 Jan;13(1):41-51
references.pmid: 18173746
references.citation: J Gastroenterol Hepatol. 1996 Mar;11(3):259-63
references.pmid: 8742923
references.citation: Gastroenterology. 2009 Apr;136(4):1368-78
references.pmid: 19249398
references.citation: Gastroenterology. 2008 Aug;135(2):591-600
references.pmid: 18558092
references.citation: Mol Cell. 2007 Jul 6;27(1):53-66
references.pmid: 17612490
references.citation: Science. 2008 Jun 13;320(5882):1492-6
references.pmid: 18556558
references.citation: Gastroenterology. 2010 May;138(5):1823-35
references.pmid: 20138039
references.citation: Mol Cell Biol. 2003 Nov;23(21):7448-59
references.pmid: 14559994
references.citation: Gastroenterology. 2005 May;128(5):1292-305
references.pmid: 15887112
references.citation: Immunity. 2004 Jul;21(1):81-93
references.pmid: 15345222
references.citation: Gastroenterology. 2010 Mar;138(3):1022-34.e1-10
references.pmid: 19962981
references.citation: EMBO J. 2009 Jun 3;28(11):1624-36
references.pmid: 19407814
references.citation: Dev Biol. 2002 Apr 15;244(2):305-18
references.pmid: 11944939
references.citation: Genes Dev. 2002 Jun 15;16(12):1488-97
references.pmid: 12080087
references.citation: Gastroenterology. 2005 Apr;128(4):935-45
references.pmid: 15825076
references.citation: Gastroenterology. 2000 Jun;118(6):1080-93
references.pmid: 10833483
references.citation: J Exp Med. 2009 Sep 28;206(10):2151-9
references.pmid: 19752183
references.citation: Gastroenterology. 2010 Feb;138(2):562-72, 572.e1-2
references.pmid: 19883649
references.citation: Cell. 2008 Sep 5;134(5):743-56
references.pmid: 18775308
references.citation: Int J Cancer. 2007 Sep 15;121(6):1182-9
references.pmid: 17520681
references.citation: Am J Pathol. 2010 Sep;177(3):1514-33
references.pmid: 20709804
references.citation: J Biol Chem. 2003 Nov 14;278(46):46138-45
references.pmid: 12963718
references.citation: Gastroenterology. 2010 Feb;138(2):550-61, 561.e1-8
references.pmid: 19909751
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18913-8
references.pmid: 19028870
references.citation: Mol Cell Biol. 2008 Jan;28(1):410-21
references.pmid: 17967878
references.citation: Nature. 2002 Jan 3;415(6867):92-6
references.pmid: 11780124
references.citation: Anat Rec. 2000 Jun 1;259(2):157-67
references.pmid: 10820318
references.citation: Curr Biol. 2010 Jan 12;20(1):9-18
references.pmid: 20045330
references.citation: Dev Biol. 2009 Jan 1;325(1):211-24
references.pmid: 19013146
references.citation: Methods. 2002 Jan;26(1):48-56
references.pmid: 12054904