Pak3 Promotes Cell Cycle Exit and Differentiation of β-Cells in the Embryonic Pancreas and Is Necessary to Maintain Glucose Homeostasis in Adult Mice

  1. Gérard Gradwohl1
  1. 1Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Development and Stem Cells, Institut National de la Santé et de la Recherche Médicale UMR 964, Centre National de Recherche Scientifique, UMR 964, Université de Strasbourg, Illkirch, France
  2. 2Neurosciences and Mental Health, The Hospital for Sick Children, Department of Physiology, University of Toronto, Toronto, Canada
  3. 3Université Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, France
  4. 4Centre National de Recherche Scientifique, UMR 8195, Orsay, France
  1. Corresponding author: Gérard Gradwohl, gradwohl{at}igbmc.fr.

Abstract

The transcription factor neurogenin3 (Ngn3) triggers islet cell differentiation in the developing pancreas. However, little is known about the molecular mechanisms coupling cell cycle exit and differentiation in Ngn3+ islet progenitors. We identified a novel effector of Ngn3 endocrinogenic function, the p21 protein–activated kinase Pak3, known to control neuronal differentiation and implicated in X-linked intellectual disability in humans. We show that Pak3 expression is initiated in Ngn3+ endocrine progenitor cells and next maintained in maturing hormone-expressing cells during pancreas development as well as in adult islet cells. In Pak3-deficient embryos, the proliferation of Ngn3+ progenitors and β-cells is transiently increased concomitantly with an upregulation of Ccnd1. β-Cell differentiation is impaired at E15.5 but resumes at later stages. Pak3-deficient mice do not develop overt diabetes but are glucose intolerant under high-fat diet (HFD). In the intestine, Pak3 is expressed in enteroendocrine cells but is not necessary for their differentiation. Our results indicate that Pak3 is a novel regulator of β-cell differentiation and function. Pak3 acts downstream of Ngn3 to promote cell cycle exit and differentiation in the embryo by a mechanism that might involve repression of Ccnd1. In the adult, Pak3 is required for the proper control of glucose homeostasis under challenging HFD.

Footnotes

  • Received March 7, 2013.
  • Accepted September 17, 2013.

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  1. Diabetes vol. 63 no. 1 203-215
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