Azzarelli, Roberta;
Hurley, Christopher;
Sznurkowska, Magdalena K;
Rulands, Steffen;
Hardwick, Laura;
Gamper, Ivonne;
Ali, Fahad;
... Philpott, Anna; + view all
(2017)
Multi-site Neurogenin3 Phosphorylation Controls Pancreatic Endocrine Differentiation.
Developmental Cell
, 41
(3)
274-286.e5.
10.1016/j.devcel.2017.04.004.
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Abstract
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 α cell generation, the earliest endocrine cell type to be formed in the developing pancreas. Moreover, un(der)phosphorylated Ngn3 maintains insulin expression in adult β 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 β cell function in the presence of pro-proliferation cues and could be manipulated to promote and maintain endocrine differentiation in vitro and in vivo.
| Type: | Article |
|---|---|
| Title: | Multi-site Neurogenin3 Phosphorylation Controls Pancreatic Endocrine Differentiation |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.devcel.2017.04.004 |
| Publisher version: | https://doi.org/10.1016/j.devcel.2017.04.004 |
| Language: | English |
| Additional information: | © 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | proneural bHLH transcription factors, endocrine differentiation, pancreatic development, β cells, neurogenin3, pancreatic organoids, insulinoma, diabetes |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10189183 |
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