Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function
- Sui Wanga,1,
- Jan N. Jensenb,1,
- Philip A. Seymourc,
- Wei Hsud,
- Yuval Dore,
- Maike Sanderc,
- Mark A. Magnusonf,
- Palle Serupb and
- Guoqiang Gua,2
- aProgram in Developmental Biology and Department of Cell and Developmental Biology, and
- fVanderbilt Center for Stem Cell Biology and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232;
- bDepartment of Developmental Biology, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark;
- cDepartment of Pediatrics and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
- dDepartment of Biomedical Genetics and Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642; and
- eDepartment of Cellular Biochemistry and Human Genetics, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
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Communicated by Douglas A. Melton, Harvard University, Cambridge, MA, April 20, 2009
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↵1S.W. and J.N.J. contributed equally to this work. (received for review August 19, 2008)
Abstract
Neurog3 (Neurogenin 3 or Ngn3) is both necessary and sufficient to induce endocrine islet cell differentiation from embryonic pancreatic progenitors. Since robust Neurog3 expression has not been detected in hormone-expressing cells, Neurog3 is used as an endocrine progenitor marker and regarded as dispensable for the function of differentiated islet cells. Here we used 3 independent lines of Neurog3 knock-in reporter mice and mRNA/protein-based assays to examine Neurog3 expression in hormone-expressing islet cells. Neurog3 mRNA and protein are detected in hormone-producing cells at both embryonic and adult stages. Significantly, inactivating Neurog3 in insulin-expressing β cells at embryonic stages or in Pdx1-expressing islet cells in adults impairs endocrine function, a phenotype that is accompanied by reduced expression of several Neurog3 target genes that are essential for islet cell differentiation, maturation, and function. These findings demonstrate that Neurog3 is required not only for initiating endocrine cell differentiation, but also for promoting islet cell maturation and maintaining islet function.
Footnotes
- 2To whom correspondence should be sent at: 465 21st Avenue South, Room 4128, Vanderbilt Medical Center, Nashville, TN 37232. E-mail: guoqiang.gu{at}vanderbilt.edu
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Author contributions: S.W., J.N.J., M.A.M., P.S., and G.G. designed research; S.W., J.N.J., P.A.S., and G.G. performed research; W.H., Y.D., M.A.M., and M.S. contributed new reagents/analytic tools; S.W., J.N.J., P.A.S., and P.S. analyzed data; and P.A.S., M.S., M.A.M., P.S., and G.G. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0904247106/DCSupplemental.
