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: The transition of gastric epithelial mucous neck cells (NCs) to digestive-enzyme-secreting zymogenic cells (ZCs) involves an increase in rough endoplasmic reticulum (rER) and formation of many large secretory vesicles. The transcription factor MIST1 is required for granulogenesis of ZCs. The transcription factor XBP1 binds the Mist1promoter and induces its expression in vitro and expands the ER in other cell types. We investigated whether XBP1 activates Mist1 to regulate ZC differentiation.
: 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 PCR, 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.
: Tamoxifen-induced deletion of Xbp1 ( Xbp1Delta) did not affect survival of ZCs but prevented formation of their structure. Xbp1DeltaZCs shrank 4-fold, compared to those of wild-type mice, with granulogenesis and cell shape abnormalities and disrupted rER. XBP1 was required and sufficient for transcriptional activation of MIST1. Despite severe structural defects, ZCs that developed in the absence of XBP1 expressed ZC markers (intrinsic factor, pepsinogen C) but did not lose expression of progenitor NC markers.
: XBP1 controls the transcriptional regulation of ZC structural development; it expands the lamellar rough ER and induces MIST1expression to regulate formation of large granules. XBP1 is also required for loss of mucous NC markers as ZCs form.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110.
This article was published in the following journal.
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Rounded or pyramidal cells of the GASTRIC GLANDS. They secrete HYDROCHLORIC ACID and produce gastric intrinsic factor, a glycoprotein that binds VITAMIN B12.
Neuroendocrine cells in the glands of the GASTRIC MUCOSA. They produce HISTAMINE and peptides such as CHROMOGRANINS. ECL cells respond to GASTRIN by releasing histamine which acts as a paracrine stimulator of the release of HYDROCHLORIC ACID from the GASTRIC PARIETAL CELLS.
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Epithelial cells that line the basal half of the GASTRIC GLANDS. Chief cells synthesize and export an inactive enzyme PEPSINOGEN which is converted into the highly proteolytic enzyme PEPSIN in the acid environment of the STOMACH.
A subtype of cholecystokinin receptor found primarily in the CENTRAL NERVOUS SYSTEM and the GASTRIC MUCOSA. It may play a role as a neuromodulator of dopaminergic neurotransmission the regulation of GASTRIC ACID secretion from GASTRIC PARIETAL CELLS.
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Enzymes are proteins that catalyze (i.e., increase the rates of) chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical re...