Multi-site Neurogenin3 Phosphorylation Controls Pancreatic Endocrine Differentiation

Publication date: Available online 27 April 2017
Source:Developmental Cell
Author(s): Roberta Azzarelli, Christopher Hurley, Magdalena K. Sznurkowska, Steffen Rulands, Laura Hardwick, Ivonne Gamper, Fahad Ali, Laura McCracken, Christopher Hindley, Fiona McDuff, Sonia Nestorowa, Richard Kemp, Kenneth Jones, Berthold Göttgens, Meritxell Huch, Gerard Evan, Benjamin D. Simons, Douglas Winton, Anna Philpott
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.

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Teaser

Azzarelli et al. show that multi-site phosphorylation of Neurogenin3 regulates pancreatic endocrine differentiation during development, and maintenance of adult β cell function in the presence of pathological pro-proliferative cues. The results suggest that dephosphorylation of Neurogenin3 may improve β cell generation in vitro and help maintain islet function in disease.


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