Essential role of Notch/Hes1 signaling in postnatal pancreatic exocrine development.

Abstract

BACKGROUND: Notch/Hes1 signaling has been shown to play a role in determining the fate of pancreatic progenitor cells. However, its function in postnatal pancreatic maturation is not fully elucidated. METHODS: We generated conditional Hes1 knockout and/or Notch intracellular domain (NICD) overexpression mice in Ptf1a- or Pdx1-positive pancreatic progenitor cells and analyzed pancreatic tissues. RESULTS: Both Ptf1a; Hes1and Ptf1a; Rosa26mice showed normal pancreatic development at P0. However, exocrine tissue of the pancreatic tail in Ptf1a; Hes1mice atrophied and was replaced by fat tissue by 4 weeks of age, with increased apoptotic cells and fewer centroacinar cells. This impaired exocrine development was completely rescued by NICD overexpression in Ptf1a; Hes1; Rosa26mice, suggesting compensation by a Notch signaling pathway other than Hes1. Conversely, Pdx1-Cre; Hes1mice showed impaired postnatal exocrine development in both the pancreatic head and tail, revealing that the timing and distribution of embryonic Hes1 expression affects postnatal exocrine tissue development. CONCLUSIONS: Notch signaling has an essential role in pancreatic progenitor cells for the postnatal maturation of exocrine tissue, partly through the formation of centroacinar cells.