DIABETES, DEFECTIVE PANCREATIC MORPHOGENESIS, AND ABNORMAL ENTEROENDOCRINE DIFFERENTIATION IN BETA2 NEUROD-DEFICIENT MICE/

Candidate transcription factors involved in pancreatic endocrine devel opment have been isolated using insulin gene regulation as a paradigm. The cell-type restricted basic helix-loop-helix (bHLH) gene, BETA2/Ne uroD, expressed in pancreatic endocrine cells, the intestine, and the brain, activates insulin gene transcription and can induce neurons to differentiate. To understand the importance of BETA2 in pancreatic end ocrine cell differentiation, mice lacking a functional BETA2 gene were generated by gene targeting experiments. Mice carrying a targeted dis ruption of the BETA2 gene developed severe diabetes and died perinatal ly. Homozygous BETA2 null mice had a striking reduction in the number of insulin-producing beta cells and failed to develop mature islets. I slet morphogenesis appeared to be arrested between E14.5 and E17.5, a period characterized by major expansion of the beta cell population. T he presence of severe diabetes in these mice suggests that proper isle t structure plays an important role in blood glucose homeostasis. In a ddition, secretin-and cholecystokinin-producing enteroendocrine cells failed to develop in the absence of BETA2. The absence of these two pa ncreatic secretagogs may explain the abnormal cellular polarity and in ability to secrete zymogen granules in pancreatic acinar exocrine cell s. The nervous system appeared to develop normally, despite abundant e xpression of BETA2 in differentiating neurons. Thus, BETA2 is critical for the normal development of several specialized cell types arising from the gut endoderm.