Phosphorylation of NEUROG3 Links Endocrine Differentiation to the Cell Cycle in Pancreatic Progenitors

During pancreatic development, proliferating pancreatic progenitors activate the proendocrine transcription factor neurogenin 3 (NEUROG3), exit the cell cycle, and differentiate into islet cells. The mechanisms that direct robust NEUROG3 expression within a subset of progenitor cells control the siz...

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Bibliographic Details
Published in:	Developmental cell 2017-04, Vol.41 (2), p.129-142.e6
Main Authors:	Krentz, Nicole A.J., van Hoof, Dennis, Li, Zhongmei, Watanabe, Akie, Tang, Mei, Nian, Cuilan, German, Michael S., Lynn, Francis C.
Format:	Article
Language:	eng
Subjects:	Animals Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - metabolism Cdkn1b Cell Cycle - physiology Cell Differentiation - physiology CRISPR/Cas9 diabetes Endocrine Cells - metabolism G1 lengthening Gene Expression Regulation, Developmental - physiology human embryonic stem cells Humans insulin Islets of Langerhans - cytology Kras Mice mouse Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Ngn3 Pancreas - cytology Pancreas - metabolism Phosphorylation - physiology Sox9-rTTA Stem Cells - cytology Stem Cells - metabolism
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Summary:	During pancreatic development, proliferating pancreatic progenitors activate the proendocrine transcription factor neurogenin 3 (NEUROG3), exit the cell cycle, and differentiate into islet cells. The mechanisms that direct robust NEUROG3 expression within a subset of progenitor cells control the size of the endocrine population. Here we demonstrate that NEUROG3 is phosphorylated within the nucleus on serine 183, which catalyzes its hyperphosphorylation and proteosomal degradation. During progression through the progenitor cell cycle, NEUROG3 phosphorylation is driven by the actions of cyclin-dependent kinases 2 and 4/6 at G1/S cell-cycle checkpoint. Using models of mouse and human pancreas development, we show that lengthening of the G1 phase of the pancreatic progenitor cell cycle is essential for proper induction of NEUROG3 and initiation of endocrine cell differentiation. In sum, these studies demonstrate that progenitor cell-cycle G1 lengthening, through its actions on stabilization of NEUROG3, is an essential variable in normal endocrine cell genesis. [Display omitted] •The progenitor cell cycle lengthens during embryonic pancreas development•Cell-cycle lengthening is essential for induction of NEUROG3•In trunk progenitors, NEUROG3 is phosphorylated by G1-S CDKs and then degraded•G1 lengthening drives endocrine differentiation by slowing NEUROG3 phosphorylation NEUROG3 is required for the formation of pancreatic endocrine cells during embryonic development. Krentz, Van Hoof et al. find that G1 lengthening occurs in pancreatic progenitors. They show that this lengthening of the cell cycle promotes NEUROG3 activity by delaying destabilizing phosphorylation of NEUROG3 by G1-S cyclin-dependent kinases.
ISSN:	1534-5807 1878-1551