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This Article Full Text Full Text (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 Google Scholar Articles by Fontanière, S. Articles by Zhang, C.-X. PubMed PubMed Citation Articles by Fontanière, S. Articles by Zhang, C.-X.

¹ CNRS UMR2501, Laboratoire Génétique Moléculaire, Signalisation et Cancer, Université Claude Bernard Lyon, Lyon F-69008, France² International Agency for Research on Cancer, 69008 Lyon, France³ INSERM U845, Faculté de Médecine, Centre de Recherche Croissance et Signalisation, Université Paris Descartes, Hôpital Necker, 75015 Paris, France⁴ Leibniz Institute for Age Research, Fritz Lipmann Institute (FLI), 07745 Jena, Germany⁵ Faculty of Biology and Pharmacy, Friedlich-Schiller-University, 07743 Jena, Germany

(Correspondence should be addressed to C-X Zhang at Laboratoire Génétique Moléculaire, Signalisation et Cancer, CNRS, UMR5201, Faculté de Médecine, Université Claude Bernard Lyon 1, 8 Avenue Rockefeller, 69373 Lyon Cedex 08, France; Email: zhang{at}sante.univ-lyon1.fr)

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene predispose patients to MEN1 that affects mainly endocrine tissues, suggesting important physiological functions of the gene in adult endocrine cells. Homozygous disruption of 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 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 - and β-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 that menin plays an indispensable role in the development of the pancreatic endocrine cells.