Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas

Abstract

Notch signaling regulates cell fate decisions in a variety of adult and embryonic tissues, and represents a characteristic feature of exocrine pancreatic cancer. In developing mouse pancreas, targeted inactivation of Notch pathway components has defined a role for Notch in regulating early endocrine differentiation, but has been less informative with respect to a possible role for Notch in regulating subsequent exocrine differentiation events. Here, we show that activated Notch and Notch target genes actively repress completion of an acinar cell differentiation program in developing mouse and zebrafish pancreas. In developing mouse pancreas, the Notch target gene Hes1 is co-expressed with Ptf1-P48 in exocrine precursor cells, but not in differentiated amylase-positive acinar cells. Using lentiviral delivery systems to induce ectopic Notch pathway activation in explant cultures of E10.5 mouse dorsal pancreatic buds, we found that both Hes1 and Notch1-IC repress acinar cell differentiation, but not Ptf1-P48 expression, in a cell-autonomous manner. Ectopic Notch activation also delays acinar cell differentiation in developing zebrafish pancreas. Further evidence of a role for endogenous Notch in regulating exocrine pancreatic differentiation was provided by examination of zebrafish embryos with homozygous mindbomb mutations, in which Notch signaling is disrupted. mindbomb-deficient embryos display accelerated differentiation of exocrine pancreas relative to wild-type clutchmate controls. A similar phenotype was induced by expression of a dominant-negative Suppressor of Hairless [Su(H)] construct, confirming that Notch actively represses acinar cell differentiation during zebrafish pancreatic development. Using transient transfection assays involving a Ptf1-responsive reporter gene, we further demonstrate that Notch and Notch/Su(H) target genes directly inhibit Ptf1 activity, independent of changes in expression of Ptf1 component proteins. These results define a normal inhibitory role for Notch in the regulation of exocrine pancreatic differentiation.

Expression of the Notch Signaling Pathway and Effect on Exocrine Cell Proliferation in Adult Rat Pancreas

“…6,7 In embryonic pancreas it has been shown before that Notch expression blocks terminal acinar cell differentiation, despite ongoing p48 expression. 34 Our data also support the observations of a recent study, in which it was shown that Notch receptors are induced in the exocrine cells during pancreas regeneration in the course of caeruleininduced pancreatitis. 19 In that experimental approach, similar dedifferentiation of the exocrine acinar cells was found.…”

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

“…High caNotch signaling, as assessed by the involvement of RBPJ-k and Hes1, promotes the trunk fate (47,48,(60)(61)(62)(63)(64). High caNotch signaling in trunk cells activates Hes1 and Sox9 (a repressor and an activator of Ngn3, respectively).…”

Endocrine pancreas development in zebrafish

“…The Notch signaling pathway maintains pancreatic progenitor cells in an undifferentiated proliferative state and controls the sequential exit of cells at defined stages to form pancreatic lineages. 65 Loss of Notch signaling in mice 66,67 and zebrafish 65,68 results in excessive early differentiating endocrine cells, leaving few progenitors available to differentiate into later appearing exocrine cells.…”