This study investigates the role of the BETA2/NeuroD gene in pancreatic development and endocrine cell differentiation in mice. Mice lacking a functional BETA2 gene developed severe diabetes and died perinatally. These mice exhibited a striking reduction in the number of insulin-producing β cells and failed to develop mature islets. Islet morphogenesis was arrested between E14.5 and E17.5, a period when the β cell population expands. The absence of BETA2 also prevented the development of secretin- and cholecystokinin-producing enteroendocrine cells, leading to abnormal cellular polarity and zymogen granule secretion in pancreatic acinar cells. Despite abundant BETA2 expression in the nervous system, mutant mice did not show neuronal defects. BETA2 is critical for the normal development of several specialized cell types arising from the gut endoderm. The study highlights the essential role of BETA2 in pancreatic islet morphogenesis and endocrine cell differentiation, as well as its involvement in the regulation of insulin and secretin gene expression. The findings suggest that BETA2 is required for the survival of endocrine islet cells and the proper organization of pancreatic islets. The BETA2 knockout mouse serves as a useful model for studying pancreatic islet cell morphogenesis and diabetes.This study investigates the role of the BETA2/NeuroD gene in pancreatic development and endocrine cell differentiation in mice. Mice lacking a functional BETA2 gene developed severe diabetes and died perinatally. These mice exhibited a striking reduction in the number of insulin-producing β cells and failed to develop mature islets. Islet morphogenesis was arrested between E14.5 and E17.5, a period when the β cell population expands. The absence of BETA2 also prevented the development of secretin- and cholecystokinin-producing enteroendocrine cells, leading to abnormal cellular polarity and zymogen granule secretion in pancreatic acinar cells. Despite abundant BETA2 expression in the nervous system, mutant mice did not show neuronal defects. BETA2 is critical for the normal development of several specialized cell types arising from the gut endoderm. The study highlights the essential role of BETA2 in pancreatic islet morphogenesis and endocrine cell differentiation, as well as its involvement in the regulation of insulin and secretin gene expression. The findings suggest that BETA2 is required for the survival of endocrine islet cells and the proper organization of pancreatic islets. The BETA2 knockout mouse serves as a useful model for studying pancreatic islet cell morphogenesis and diabetes.