Notch signaling controls multiple steps of pancreatic differentiation

TLDR

Multiple pancreatic cell types arise asynchronously during embryogenesis, requiring temporal changes in progenitor potential, and Notch signaling modulates this differentiation but its timing and mechanisms remain unclear. The study establishes a modular transgenic system to heritably activate Notch1 in pancreatic progenitors and differentiated cells. This system enables controlled Notch1 activation across multiple progenitor and differentiated cell types. Activated Notch1 expression in Pdx1 progenitors blocks both exocrine and endocrine differentiation, keeping progenitors undifferentiated even when induced after pancreas specification, while endocrine precursors require Notch inhibition for differentiation, whereas mature endocrine cells are resistant.

Abstract

Multiple cell types of the pancreas appear asynchronously during embryogenesis, which requires that pancreatic progenitor cell potential changes over time. Loss-of-function studies have shown that Notch signaling modulates the differentiation of these progenitors, but it remains unclear how and when the Notch pathway acts. We established a modular transgenic system to heritably activate mouse Notch1 in multiple types of progenitors and differentiated cells. We find that misexpression of activated Notch in Pdx1 -expressing progenitor cells prevents differentiation of both exocrine and endocrine lineages. Progenitors remain trapped in an undifferentiated state even if Notch activation occurs long after the pancreas has been specified. Furthermore, endocrine differentiation is associated with escape from this activity, because Ngn3 -expressing endocrine precursors are susceptible to Notch inhibition, whereas fully differentiated endocrine cells are resistant.