Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function

June 16, 2009
106 (24) 9715-9720

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.

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Acknowledgments.

We thank Susan B. Hipkens, Kathy D. Shelton, Yanwen Xu, and Aizhen Zhao for technical assistance.; Chris Wright for help with writing the manuscript; and the Vanderbilt Transgenic/ES Cell Shared Resource for expertly performing blastocyst microinjections. We are also grateful to John Hutton for the use of his laboratory during establishment of the Neurog3tTA line. This research was supported by National Institutes of Health Grants DK065949 (to G.G.), DK072473 (to M.A.M.), DK072495 and DK68471 (to M.S.), and DK072495 (to P.S.); and Juvenile Diabetes Research Foundation Grant 2007-712 (to G.G.). P.S. was supported by the Juvenile Diabetes Research Foundation and the European Union 6th Framework Program. P.A.S. was supported by a Juvenile Diabetes Research Foundation postdoctoral fellowship (3-2004-608). J.N.J was supported by the Danish Research Counsel (271-05-0667), the Carlsberg Foundation, and a Julie von Müllens fund.

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 106 | No. 24
June 16, 2009
PubMed: 19487660

Classifications

Submission history

Received: August 19, 2008
Published online: June 16, 2009
Published in issue: June 16, 2009

Keywords

  1. endocrine progenitor
  2. maintenance
  3. pancreas
  4. diabetes
  5. sugar metabolism

Acknowledgments

We thank Susan B. Hipkens, Kathy D. Shelton, Yanwen Xu, and Aizhen Zhao for technical assistance.; Chris Wright for help with writing the manuscript; and the Vanderbilt Transgenic/ES Cell Shared Resource for expertly performing blastocyst microinjections. We are also grateful to John Hutton for the use of his laboratory during establishment of the Neurog3tTA line. This research was supported by National Institutes of Health Grants DK065949 (to G.G.), DK072473 (to M.A.M.), DK072495 and DK68471 (to M.S.), and DK072495 (to P.S.); and Juvenile Diabetes Research Foundation Grant 2007-712 (to G.G.). P.S. was supported by the Juvenile Diabetes Research Foundation and the European Union 6th Framework Program. P.A.S. was supported by a Juvenile Diabetes Research Foundation postdoctoral fellowship (3-2004-608). J.N.J was supported by the Danish Research Counsel (271-05-0667), the Carlsberg Foundation, and a Julie von Müllens fund.

Notes

This article contains supporting information online at www.pnas.org/cgi/content/full/0904247106/DCSupplemental.

Authors

Affiliations

Sui Wang1
Program in Developmental Biology and Department of Cell and Developmental Biology, and
Jan N. Jensen1
Department of Developmental Biology, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark;
Philip A. Seymour
Department of Pediatrics and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
Wei Hsu
Department of Biomedical Genetics and Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642; and
Yuval Dor
Department of Cellular Biochemistry and Human Genetics, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
Maike Sander
Department of Pediatrics and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
Mark A. Magnuson
Vanderbilt Center for Stem Cell Biology and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232;
Palle Serup
Department of Developmental Biology, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark;
Program in Developmental Biology and Department of Cell and Developmental Biology, and

Notes

2
To whom correspondence should be sent at: 465 21st Avenue South, Room 4128, Vanderbilt Medical Center, Nashville, TN 37232. E-mail: [email protected]
Communicated by Douglas A. Melton, Harvard University, Cambridge, MA, April 20, 2009
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.
1
S.W. and J.N.J. contributed equally to this work.

Competing Interests

The authors declare no conflict of interest.

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    Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function
    Proceedings of the National Academy of Sciences
    • Vol. 106
    • No. 24
    • pp. 9537-9932

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