FOXO1 Is Present in Stomach Epithelium and Determines Gastric Cell Distribution

Authors

Wendy M McKimpson
Taiyi Kuo
Takumi Kitamoto
Sei Higuchi
Jason C Mills
Rebecca A Haeusler
Domenico Accili

Publication Date

1-1-2022

Journal

Gastro Hep Advances

DOI

10.1016/j.gastha.2022.05.005

PMID

36117550

PMCID

PMC9481069

PubMedCentral® Posted Date

5-14-2022

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Enteroendocrine Cells, Diabetes Treatment, Cell Cycle, Parietal Cells, Transcription Factor

Abstract

BACKGROUND AND AIMS: Stomach cells can be converted to insulin-producing cells by Neurog3, MafA, and Pdxl over-expression. Enteroendocrine cells can be similarly made to produce insulin by the deletion of FOXO1. Characteristics and functional properties of FOXO1-expressing stomach cells are not known.

METHODS: Using mice bearing a FOXO1-GFP knock-in allele and primary cell cultures, we examined the identity of FOXO1-expressing stomach cells and analyzed their features through loss-of-function studies with red-to-green fluorescent reporters.

RESULTS: FOXO1 localizes to a subset of Neurog3 and parietal cells. FOXO1 deletion ex vivo or in vivo using Neurog3-cre or Atp4b-cre increased numbers of parietal cells, generated insulin- and C-peptide-immunoreactive cells, and raised Neurog3 messenger RNA. Gene expression and ChIP- seq experiments identified the cell cycle regulator cyclin E1 (CCNE1) as a FOXO1 target.

CONCLUSION: FOXO1 is expressed in a subset of stomach cells. Its ablation increases parietal cells and yields insulin-immunoreactive cells, consistent with a role in lineage determination.