Abstract
During early pancreatic development, Notch signaling represses differentiation of endocrine cells and promotes proliferation of Nkx6-1 +Ptf1a+ multipotent progenitor cells (MPCs). Later, antagonistic interactions between Nkx6 transcription factors and Ptf1a function to segregate MPCs into distal Nkx6-1-Ptf1a+ acinar progenitors and proximal Nkx6-1+Ptf1a- duct and β-cell progenitors. Distal cells are initially multipotent, but evolve into unipotent, acinar cell progenitors. Conversely, proximal cells are bipotent and give rise to duct cells and late-born endocrine cells, including the insulin producing β-cells. However, signals that regulate proximodistal (P-D) patterning and thus formation of β-cell progenitors are unknown. Here we show that Mind bomb 1 (Mib1) is required for correct P-D patterning of the developing pancreas and β-cell formation. We found that endoderm-specific inactivation of Mib1 caused a loss of Nkx6-1+Ptf1a- and Hnf1β+ cells and a corresponding loss of Neurog3+ endocrine progenitors and β-cells. An accompanying increase in Nkx6-1 -Ptf1a+ and amylase+ cells, occupying the proximal domain, suggests that proximal cells adopt a distal fate in the absence of Mib1 activity. Impeding Notch-mediated transcriptional activation by conditional expression of dominant negative Mastermind-like 1 (Maml1) resulted in a similarly distorted P-D patterning and suppressed β-cell formation, as did conditional inactivation of the Notch target gene Hes1. Our results reveal iterative use of Notch in pancreatic development to ensure correct P-D patterning and adequate β-cell formation.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Proceedings of the National Academy of Sciences USA (PNAS) |
| Vol/bind | 109 |
| Udgave nummer | 19 |
| Sider (fra-til) | 7356-61 |
| Antal sider | 6 |
| ISSN | 0027-8424 |
| DOI | |
| Status | Udgivet - 8 maj 2012 |