Abstract
Notch signaling is known to control early pancreatic differentiation through Ngn3 repression. In later stages, downstream of Notch, the Presenilins are still required to maintain the endocrine fate allocation. Amongst their multiple targets, it remains unclear which one actually controls the maintenance of the fate of the early islets. Conditional deletions of the Notch effector RBP-Jκ with lineage tracing in Presenilin-deficient endocrine progenitors, demonstrated that this factor is central to the control of the fate through a non-canonical Notch mechanism. RBP-Jκ mice exhibit normal islet morphogenesis and function, however, a fraction of the progenitors fails to differentiate and develop into disorganized masses resembling acinar to ductal metaplasia and chronic pancreatitis. A subsequent deletion of RBP-Jκ in forming β-cells led to the transdifferentiation into the other endocrine cells types, indicating that this factor still mediates the maintenance of the fate within the endocrine lineage itself. These results highlight the dual importance of Notch signaling for the endocrine lineage. Even after Ngn3 expression, Notch activity is required to maintain both fate and maturation of the Ngn3 progenitors. In a subset of the cells, these alterations of Notch signaling halt their differentiation and leads to acinar to ductal metaplasia.
Highlights
The pancreas develops from Pdx[1] and Ptf1a-expressing progenitors in the foregut
We had previously hypothesized that fate control could result from a competition between Notch Intra Cellular Domain (NICD) and Ptf1a for RBP-Jκ7
NICD would be required to sequester RBP-Jκaway from Ptf1a in order to prevent the promotion of the acinar fate in this lineage
Summary
The pancreas develops from Pdx[1] and Ptf1a-expressing progenitors in the foregut. An integrated network of transcription factors acts in concert during pancreatogenesis to carefully balance the maturation of these progenitors between the endocrine, acinar, and ductal lineage. Lowering Notch signaling in these cells could divert them towards the acinar fate This non-canonical mechanism, associated to the fact that Ptf1a was still present in these cells strongly suggested that Notch needs to be activated to sequester RBP-Jκaway from Ptf1a in Ngn[3] progenitors to prevent the promotion of the acinar program[7]. In these studies, we demonstrated that RBP-Jκ, the downstream Notch effector, is central to the early fate-maintenance of the endocrine progenitors. Conditional deletion of RBP-Jκcan revert the Presenilin phenotype and maintain the Ngn[3] progenitors within their original endocrine lineage again even though all Notch signaling is prevented
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