GENETIC-ANALYSIS REVEALS THAT PAX6 IS REQUIRED FOR NORMAL TRANSCRIPTION OF PANCREATIC HORMONE GENES AND ISLET DEVELOPMENT

We present genetic and biochemical evidence that PAX6 is a key regulat or of pancreatic islet hormone gene transcription and is required for normal islet development. In embryos homozygous for a mutant allele of the Pax6 gene, Small eye (Sey(Neu)), the numbers of all four types of endocrine cells in the pancreas are decreased significantly, and isle t morphology is abnormal. In the remaining islet cells, hormone produc tion, particularly glucagon production, is markedly reduced because of decreased gene transcription. These effects appear to result from a l ack of PAX6 protein in the mutant embryos. Biochemical studies identif y wild-type PAX6 protein as the transcription factor that binds to a c ommon element in the glucagon, insulin, and somatostatin promoters, an d show that PAX6 transactivates the glucagon and insulin promoters.