| First Author | Azzarelli R | Year | 2017 |
| Journal | Dev Cell | Volume | 41 |
| Issue | 3 | Pages | 274-286.e5 |
| PubMed ID | 28457793 | Mgi Jnum | J:241637 |
| Mgi Id | MGI:5903322 | Doi | 10.1016/j.devcel.2017.04.004 |
| Citation | Azzarelli R, et al. (2017) Multi-site Neurogenin3 Phosphorylation Controls Pancreatic Endocrine Differentiation. Dev Cell 41(3):274-286.e5 |
| abstractText | The proneural transcription factor Neurogenin3 (Ngn3) plays a critical role in pancreatic endocrine cell differentiation, although regulation of Ngn3 protein is largely unexplored. Here we demonstrate that Ngn3 protein undergoes cyclin-dependent kinase (Cdk)-mediated phosphorylation on multiple serine-proline sites. Replacing wild-type protein with a phosphomutant form of Ngn3 increases alpha cell generation, the earliest endocrine cell type to be formed in the developing pancreas. Moreover, un(der)phosphorylated Ngn3 maintains insulin expression in adult beta cells in the presence of elevated c-Myc and enhances endocrine specification during ductal reprogramming. Mechanistically, preventing multi-site phosphorylation enhances both Ngn3 stability and DNA binding, promoting the increased expression of target genes that drive differentiation. Therefore, multi-site phosphorylation of Ngn3 controls its ability to promote pancreatic endocrine differentiation and to maintain beta cell function in the presence of pro-proliferation cues and could be manipulated to promote and maintain endocrine differentiation in vitro and in vivo. |
