title: Hepatocyte nuclear factor 4α is required for cell differentiation and homeostasis in the adult mouse gastric epithelium.
abstract: We have previously shown that the sequential transcription factors Xbp1→Mist1 (Bhlha15) govern the ultrastructural maturation of the secretory apparatus in enzyme-secreting zymogenic chief cells (ZCs) in the gastric unit. Here we sought to identify transcriptional regulators upstream of X-box binding protein 1 (XBP1) and MIST1. We used immunohistochemistry to characterize Hnf4α(flox/flox) adult mouse stomachs after tamoxifen-induced deletion of Hnf4α We used qRT-PCR, Western blotting, and chromatin immunoprecipitation to define the molecular interaction between hepatocyte nuclear factor 4 alpha (HNF4α) and Xbp1 in mouse stomach and human gastric cells. We show that HNF4α protein is expressed in pit (foveolar) cells, mucous neck cells, and zymogenic chief cells (ZCs) of the corpus gastric unit. Loss of HNF4α in adult mouse stomach led to reduced ZC size and ER content, phenocopying previously characterized effects of Xbp1 deletion. However, HNF4α(Δ/Δ) stomachs also exhibited additional phenotypes including increased proliferation in the isthmal stem cell zone and altered mucous neck cell migration, indicating a role of HNF4α in progenitor cells as well as in ZCs. HNF4α directly occupies the Xbp1 promoter locus in mouse stomach, and forced HNF4α expression increased abundance of XBP1 mRNA in human gastric cancer cells. Finally, as expected, loss of HNF4α caused decreased Xbp1 and Mist1 expression in mouse stomachs. We show that HNF4α regulates homeostatic proliferation in the gastric epithelium and is both necessary and sufficient for the upstream regulation of the Xbp1→Mist1 axis in maintenance of ZC secretory architecture.
authors.affiliation: Division of Gastroenterology, Departments of Medicine, Pathology and Immunology, and Developmental Biology, Washington University, St. Louis, Missouri.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Moore
authors.affiliation: Division of Gastroenterology, Departments of Medicine, Pathology and Immunology, and Developmental Biology, Washington University, St. Louis, Missouri.
authors.forename: Shradha S
authors.initials: SS
authors.lastname: Khurana
authors.affiliation: Division of Gastroenterology, Departments of Medicine, Pathology and Immunology, and Developmental Biology, Washington University, St. Louis, Missouri.
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Huh
authors.affiliation: Division of Gastroenterology, Departments of Medicine, Pathology and Immunology, and Developmental Biology, Washington University, St. Louis, Missouri jmills@wustl.edu.
authors.forename: Jason C
authors.identifier: 0000-0002-0402-4662
authors.initials: JC
authors.lastname: Mills
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D018345:Mice, Knockout; D010641:Phenotype; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014162:Transfection; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051557:Hepatocyte Nuclear Factor 4; D000071717:X-Box Binding Protein 1; C491312:Bhlha15 protein, mouse; C496592:HNF4A protein, human; C496593:Hnf4a protein, mouse; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse
keywords: mucous neck cell; scaling factor; secretory cells