GATA factors promote ER integrity and ?-cell survival and contribute to type 1 diabetes risk.

ABSTRACT: Pancreatic ?-cell survival remains poorly understood despite decades of research. GATA transcription factors broadly regulate embryogenesis and influence survival of several cell types, but their role in adult ?-cells remains undefined. To investigate the role of GATA factors in adult ?-cells, we derived ?-cell-inducible Gata4- and Gata6-knockout mice, along with whole-body inducible Gata4 knockouts. ?-Cell Gata4 deletion modestly increased the proportion of dying ?-cells in situ with ultrastructural abnormalities suggesting endoplasmic reticulum (ER) stress. Notably, glucose homeostasis was not grossly altered in Gata4- and Gata6-knockout mice, suggesting that GATA factors do not have essential roles in ?-cells. Several ER stress signals were up-regulated in Gata4 and Gata6 knockouts, most notably CHOP, a known regulator of ER stress-induced apoptosis. However, ER stress signals were not elevated to levels observed after acute thapsigargin administration, suggesting that GATA deficiency only caused mild ER stress. Simultaneous deletion of Gata4 and CHOP partially restored ?-cell survival. In contrast, whole-body inducible Gata4 knockouts displayed no evidence of ER stress in other GATA4-enriched tissues, such as heart. Indeed, distinct GATA transcriptional targets were differentially expressed in islets compared with heart. Such ?-cell-specific findings prompted study of a large meta-analysis dataset to investigate single nucleotide polymorphisms harbored within the human GATA4 locus, revealing several variants significantly associated with type 1 diabetes mellitus. We conclude that GATA factors have important but nonessential roles to promote ER integrity and ?-cell survival in a tissue-specific manner and that GATA factors likely contribute to type 1 diabetes mellitus pathogenesis.

SUBMITTER: Sartori DJ 

PROVIDER: S-EPMC3874454 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature