| First Author | Moore BD | Year | 2016 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 311 |
| Issue | 2 | Pages | G267-75 |
| PubMed ID | 27340127 | Mgi Jnum | J:239963 |
| Mgi Id | MGI:5882140 | Doi | 10.1152/ajpgi.00195.2016 |
| Citation | Moore BD, et al. (2016) Hepatocyte nuclear factor 4alpha is required for cell differentiation and homeostasis in the adult mouse gastric epithelium. Am J Physiol Gastrointest Liver Physiol 311(2):G267-75 |
| abstractText | 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 Hnf4alpha(flox/flox) adult mouse stomachs after tamoxifen-induced deletion of Hnf4alpha We used qRT-PCR, Western blotting, and chromatin immunoprecipitation to define the molecular interaction between hepatocyte nuclear factor 4 alpha (HNF4alpha) and Xbp1 in mouse stomach and human gastric cells. We show that HNF4alpha protein is expressed in pit (foveolar) cells, mucous neck cells, and zymogenic chief cells (ZCs) of the corpus gastric unit. Loss of HNF4alpha in adult mouse stomach led to reduced ZC size and ER content, phenocopying previously characterized effects of Xbp1 deletion. However, HNF4alpha(Delta/Delta) stomachs also exhibited additional phenotypes including increased proliferation in the isthmal stem cell zone and altered mucous neck cell migration, indicating a role of HNF4alpha in progenitor cells as well as in ZCs. HNF4alpha directly occupies the Xbp1 promoter locus in mouse stomach, and forced HNF4alpha expression increased abundance of XBP1 mRNA in human gastric cancer cells. Finally, as expected, loss of HNF4alpha caused decreased Xbp1 and Mist1 expression in mouse stomachs. We show that HNF4alpha 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. |
