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This Article Accepted manuscript (PDF) Supplementary figures All Versions of this Article: JOE-08-0289v1 199/2/287    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fontaniere, S. Articles by Zhang, C. Search for Related Content PubMed PubMed Citation Articles by Fontaniere, S. Articles by Zhang, C.

S Fontaniere, Laboratoire Genetique et cancer, Unnviersite Lyon 1, Lyon, France
B Duvillie, INSERM E363, University Paris-Descartes, Faculty of Medicine, Necker Hospital, Paris, France
R Scharfmann, Faculty of Medicine, INSERM, Necker Hospital, University Paris-Descartes, Paris, France
C Carreira, Laboratoire Genetique et Cancer , CNRS, UMR5201, Universite lyon1, Lyon, France
Z Wang, Leibniz Institute for Age Research, Fritz Lipmann Institute, jena, Germany
C Zhang, Laboratoire Genetique et Cancer, CNRS, UMR5201, Lyon, France

Correspondence: Cx Zhang, Email: zhang{at}sante.univ-lyon1.fr

Abstract

Mutations of the MEN1 gene predispose patients to Multiple Endocrine Neoplasia type 1 (MEN1) which affects mainly endocrine tissues, suggesting important physiological functions of the gene in adult endocrine cells. Homozygous disruption of the Men1 in mice causes embryonic lethality, whereas the eventual involvement of the gene in embryonic development of the endocrine cells remains unknown. Here we show that homozygous Men1 knockout mice demonstrate a reduced number of glucagon-positive cells in the E12.5 pancreatic bud associated with apoptosis, whereas the the exocrine pancreas development in these mice is not affected. Our data suggest that MENIN is involved in the survival of the early pancreatic endocrine cells during the first developmental transition. Furthermore, chimerism assay revealed that MENIN has an autonomous and specific effect on the development of islet cells. In addition, using pancreatic bud culture mimicking the differentiation of alpha and beta-cells during the second transition, we show that loss of MENIN leads to the failure of endocrine cell development, altered pancreatic structure, and a markedly decreased number of cells expressing Neurogenin 3, indicating that MENIN is also required at this stage of the endocrine pancreas development. Taken together, our results suggest an indispensable role played by MENIN in development of the pancreatic endocrine cells.