Notch signalling controls pancreatic cell differentiation

The pancreas contains both exocrine and endocrine cells, but the molecular mechanisms controlling the differentiation of these cell types are largely unknown. Despite their endodermal origin, pancreatic endocrine cells share several molecular characteristics with neurons(1-5), and, like neurons in t he central nervous system(6,7) differentiating endocrine cells in the pancr eas appear in a scattered fashion within a field of progenitor coils(8,9). This indicates that they may be generated by lateral specification through Notch signalling(6,7). Here, to test this idea, we analysed pancreas develo pment in mice genetically altered at several steps in the Notch signalling pathway, Mice deficient for Delta-like gene 1 (Dll1)(10) or the intracellul ar mediator RBP-JK(11) showed accelerated differentiation of pancreatic end ocrine cells. A similar phenotype was observed in mice over-expressing neur ogenin 3 (ngn 3)(12) or the intracellular form of Notch3 (ref. 13) (a repre ssor of Notch signalling). These data provide evidence that ngn3 acts as pr o-endocrine gene and that Notch signalling is critical for the decision bet ween the endocrine and progenitor/exocrine fates in the developing pancreas .