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Multi-site Neurogenin3 Phosphorylation Controls Pancreatic Endocrine Differentiation.

Developmental cell | 2017

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.

Pubmed ID: 28457793 RIS Download

Associated grants

  • Agency: Medical Research Council, United Kingdom
    Id: MC_PC_12009
  • Agency: Medical Research Council, United Kingdom
    Id: 1509287
  • Agency: Wellcome Trust, United Kingdom
    Id: 098357/Z/12/Z
  • Agency: Cancer Research UK, United Kingdom
    Id: 12077
  • Agency: Medical Research Council, United Kingdom
    Id: MR/M008975/1
  • Agency: Wellcome Trust, United Kingdom
    Id: 104151/Z/14/A
  • Agency: Medical Research Council, United Kingdom
    Id: MR/K018329/1
  • Agency: Wellcome Trust, United Kingdom
  • Agency: Wellcome Trust, United Kingdom
    Id: 097922/Z/11/Z
  • Agency: Medical Research Council, United Kingdom
    Id: MR/L021129/1

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