Murine Perinatal β-Cell Proliferation and the Differentiation of Human Stem Cell-Derived Insulin-Expressing Cells Require NEUROD1

Inactivation of the beta-cell transcription factor NEUROD1 causes diabetes in mice and humans. In this study, we uncovered novel functions of NEUROD1 during murine islet cell development and during the differentiation of human embryonic stem cells (HESCs) into insulin-producing cells. In mice, we determined that Neurod1 is required for perinatal proliferation of alpha- and beta-cells. Surprisingly, apoptosis only makes a minor contribution to beta-cell loss when Neurod1 is deleted. Inactivation of NEUROD1 in HESCs severely impaired their differentiation from pancreatic progenitors into insulin-expressing (HESC-beta) cells; however, survival or proliferation was not affected at the time points analyzed. NEUROD1 was also required in HESC-beta cells for the full activation of an essential beta-cell transcription factor network. These data reveal conserved and distinct functions of NEUROD1 during mouse and human beta-cell development and maturation, with important implications about the function of NEUROD1 in diabetes.