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^cre/+; Hes1^f/f and Ptf1a^cre/+; Rosa26^NICD mice showed normal pancreatic development at P0. However, exocrine tissue of the pancreatic tail in Ptf1a^cre/+; Hes1^f/f mice 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^cre/+; Hes1^f/f; Rosa26^NICD mice, suggesting compensation by a Notch signaling pathway other than Hes1. Conversely, Pdx1-Cre; Hes1^f/f mice 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.

Keywords: Centroacinar cell; Hes1; Notch signaling; Pancreas; Postnatal development.