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Human Molecular Genetics Advance Access originally published online on October 21, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3307-3314
DOI: 10.1093/hmg/ddg355
© 2003 Oxford University Press

Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas

Miguel A. Maestro1, Sylvia F. Boj1, Reini F. Luco1, Christophe E. Pierreux3, Judit Cabedo1, Joan M. Servitja1, Michael S. German2, Guy G. Rousseau3, Frédéric P. Lemaigre3 and Jorge Ferrer1,*

1Endocrinology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain, 2Hormone Research Institute, University of California, San Francisco, CA, USA and 3Hormone and Metabolic Research Unit, Université Catholique de Louvain and Institute of Cellular Pathology, Brussels, Belgium

Received July 28, 2003; Accepted October 15, 2003

During pancreatic organogenesis endocrine cells arise from non self-renewing progenitors that express Ngn3. The precursors that give rise to Ngn3+ cells are presumably located within duct-like structures. However, the nature of such precursors is poorly understood. We show that, at E13–E18, the embryonic stage during which the major burst of ß-cell neogenesis takes place, pancreatic duct cells express Hnf1ß, the product of the maturity-onset diabetes of the young type 5 (MODY5) gene. Ngn3+ cells at this stage invariably cluster with mitotically competent Hnf1ß+ cells, and are often intercalated with these cells in the epithelium that lines the lumen of primitive ducts. We present several observations that collectively indicate that Hnf1ß+ cells are the immediate precursors of Ngn3+ cells. We furthermore show that Hnf1ß expression is markedly reduced in early pancreatic epithelial cells of Hnf6-deficient mice, in which formation of Ngn3+ cells is defective. These findings define a precursor cellular stage of the embryonic pancreas and place Hnf1ß in a genetic hierarchy that regulates the generation of pancreatic endocrine cells.

* To whom correspondence should be addressed at: Endocrinology, Hospital Clínic i Universitari, Villarroel 170, Barcelona-08036, Spain. Tel: +34 2275400(3028); Fax: +34 934516638; Email: jferrer{at}medicina.ub.es


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