Abstract
Pancreatic β-cells arise from bipotent trunk progenitors (TrPCs) that are specified from multipotent pancreatic progenitors (MPCs) in a Notch-dependent manner. The time window during which Notch signaling is required to specify TrPCs and the identity of the Notch ligands required for this patterning process remain obscure. Here we show that blocking Notch signal transduction before E13 drives progenitors to an acinar fate while blockade after E13 results in amplified and accelerated endocrine differentiation. Mapping of Dll1 and Jag1 expression using IF and novel targeted reporters revealed that uniform Jag1 expression in E10.5 MPCs becomes restricted to distal Ptf1a+ tip progenitors (TiPCs) during PD patterning. Conversely, Dll1 is expressed in scattered MPCs, TrPCs, and TiPCs, and in Neurog3+ endocrine precursors at all stages. Endodermal deletion of Jag1 delays resoln. of tip and trunk domains, and at E15.5 distal Sox9+ TrPCs are replaced by Ptf1a+ Mist1+ cells. Remarkably, this occurred with negligible impact on pancreas size and gross morphol. of the ductal tree despite the replacement of TrPCs with TiPCs in the duct-lining epithelium. Some Sox9+ progenitors remain proximally in the prospective main duct and loss of β-cells is not complete. However, endodermal deletion of Dll1 and Jag1 ablated the remaining Sox9+ TrPCs and β-cells entirely at E15.5, while normal specification of Sox9+ TrPCs was seen in Dll1 single mutants. Together, our results reveal a shift in competence of Hnf1β+ progenitors around E13 and show that multiple cellular sources provide Notch ligand input to specify different parts of the pancreatic epithelium prior to E13. [on SciFinder(R)]
| Original language | English |
|---|---|
| Journal | bioRxiv, Developmental Biology |
| Pages (from-to) | 1-36 |
| Number of pages | 36 |
| DOIs | |
| Publication status | E-pub ahead of print - 2018 |