Pancreatic Cell Fate Determination Relies on Notch Ligand Trafficking by NFIA

Summary: Notch is activated globally in pancreatic progenitors; however, for progenitors to differentiate into endocrine cells, they must escape Notch activation to express Neurogenin-3. Here, we find that the transcription factor nuclear factor I/A (NFIA) promotes endocrine development by regulating Notch ligand Dll1 trafficking. Pancreatic deletion of NFIA leads to cell fate defects, with increased duct and decreased endocrine formation, while ectopic expression promotes endocrine formation in mice and human pancreatic progenitors. NFIA-deficient mice exhibit dysregulation of trafficking-related genes including increased expression of Mib1, which acts to target Dll1 for endocytosis. We find that NFIA binds to the Mib1 promoter, with loss of NFIA leading to an increase in Dll1 internalization and enhanced Notch activation with rescue of the cell fate defects after Mib1 knockdown. This study reveals NFIA as a pro-endocrine factor in the pancreas, acting to repress Mib1, inhibit Dll1 endocytosis and thus promote escape from Notch activation. : Scavuzzo et al. show NFIA is expressed at the onset of the secondary transition in pancreatic progenitors to regulate endocrine fate induction. NFIA binds the Mib1 promoter, with increased Mib1 in NFIA-deficient cells, more Dll1 endocytosis, and higher Notch activation, leading to formation of more ducts and fewer endocrine cells. Keywords: development, pancreas, cell fate, endocrine cell, Notch signaling, NFIA, Mib1, endocytosis