XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum.
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.
Huh
Won Jae
WJ
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
Esen
Emel
E
Geahlen
Jessica H
JH
Bredemeyer
Andrew J
AJ
Lee
Ann-Hwee
AH
Shi
Guanglu
G
Konieczny
Stephen F
SF
Glimcher
Laurie H
LH
Mills
Jason C
JC
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
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
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