The role of Foxa2 in the pancreatic β cell

Abstract

Glucose homeostasis is a tightly-regulated process involving multiple tissues in the body. The pancreas is an endoderm-derived organ responsible for glucose-sensing as well as the subsequent secretion of insulin, the hormone responsible for the promotion of glucose uptake and restoring glucose levels to physiological baseline. Foxa2 (Forkhead box a2 ) encodes a winged-helix transcription factor expressed in the pancreas during embryogenesis and throughout adulthood. Foxa2 is a known transcriptional regulator and is necessary for murine survival beyond embryonic day 11 (E11). Because of the early lethality of Foxa2 −/− mice, the precise role of this gene in pancreatic function has not yet been fully elucidated. To investigate the role of Foxa2 in the pancreas, a mouse model harboring a β cell-specific deletion was generated which utilizes Cre recombinase under control of the rat Insulin 2 promoter to delete Foxa2 as early as E14.5. Foxa2 loxP/loxP;Ins.Cre mice are growth-delayed and succumb to hyperinsulinemic hypoglycemia 7–12 days after birth. Along with improper calcium influx and insulin secretion from mutant islets in response to glucose and amino acids, my findings reveal several targets of Foxa2, including Sur1 and Kir6.2, the components of the KATP channel. One additional target, Hadhsc, encodes an enzyme involved in fatty acid oxidation. Interestingly, the human orthologues of these three genes, SUR1, KIR6.2, and SCHAD, are mutated in some patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI). A second model, under current investigation, has three genetics requirements and will utilize the drug doxycycline as part of the Tet-On™ Gene Expression System to inducibly delete Foxa2 in adult mice. Utilizing the Z/AP reporter line with alkaline phosphatase as a readout of Cre activity, I chose an effective transgenic promoter line to facilitate the β cell-specific deletion of Foxa2 at the timepoint(s) of our choice. Through comparison of a series of physiological tests conducted before and after doxycycline treatment (Foxa2 deletion), I will soon be able to assess the role of Foxa2 in adult mice. Although further investigation is necessary, these studies will further elucidate the role of Foxa2 in the pancreas and strengthen our understanding of the regulation of glucose homeostasis