Inactivation of the winged helix transcription factor HNF3 alpha affects glucose homeostasis and islet glucagon gene expression in vivo

Mice homozygous for a null mutation in the winged helix transcription facto r HNF3 alpha showed severe postnatal growth retardation followed by death b etween P2 and P12. Homozygous mutant mice were hypoglycemic despite unchang ed expression of HNF3 target genes involved in hepatic gluconeogenesis. Whe reas insulin and corticosteroid levels were altered as expected, plasma glu cagon was reduced markedly in the mutant animals despite the hypoglycemia t hat should be expected to increase glucagon levels. This correlated with a 70% reduction in pancreatic proglucagon gene expression. We also showed tha t HNF3 alpha could bind to and transactivate the proglucagon gene promoter. These observations invoke a central role for HNF3a in the regulatory contr ol of islet genes essential for glucose homeostasis in vivo.