Abstract
During pancreas development, endocrine and exocrine cells arise from a common multipotent progenitor pool. How these cell fate decisions are coordinated with tissue morphogenesis is poorly understood. Here we have examined ductal morphology, endocrine progenitor cell fate and Notch signaling in Ngn3-/- mice, which do not produce islet cells. Ngn3 deficiency results in reduced branching and enlarged pancreatic duct-like structures, concomitant with Ngn3 promoter activation throughout the ductal epithelium and reduced Notch signaling. Conversely, forced generation of surplus endocrine progenitor cells causes reduced duct caliber and an excessive number of tip cells. Thus, endocrine progenitor cells normally provide a feedback signal to adjacent multipotent ductal progenitor cells that activates Notch signaling, inhibits further endocrine differentiation and promotes proper morphogenesis. These results uncover a novel layer of regulation coordinating pancreas morphogenesis and endocrine/exocrine differentiation, and suggest ways to enhance the yield of beta cells from stem cells.
| Original language | English |
|---|---|
| Pages (from-to) | 26-36 |
| Number of pages | 11 |
| Journal | Developmental Biology |
| Volume | 359 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1 Nov 2011 |
Bibliographical note
Funding Information:We thank Abraham Fainsod, Ze'ev Paroush, Klaus Kaestner, Jan Jensen and Palle Serup for stimulating discussions. We thank Maike Sander, Chris Wright and Christoph Kellendonk for generous gifts of Ngn3, Pdx1 and Cre antibodies and Holger Russ for help with dissection of Pax6 mutant embryos. Supported by grants from JDRF , the Helmsley Foundation , the Union Seventh Framework Programme under grant agreement no. 241883 , ERC starting grant and the Dutch Friends of Hebrew University to YD.
Keywords
- Branching morphogenesis
- Jagged1
- Lateral inhibition
- Lineage tracing
- Neurogenin3
- Notch
- Pancreas development