Rfx6 directs islet formation and insulin production in mice and humans

Stuart B. Smith, Hui-Qi Qu, Nadine Taleb, Nina Y. Kishimoto, David W. Scheel, Yang Lu, Ann-Marie Patch, Rosemary Grabs, Juehu Wang, Francis C. Lynn, Takeshi Miyatsuka, John Mitchell, Rina Seerke, Julie Désir, Serge Vanden Eijnden, Marc Abramowicz, Nadine Kacet, Jacques Weill, Marie-Ève Renard, Mattia Gentile, Inger Hansen, Ken Dewar, Andrew T. Hattersley, Rennian Wang, Maria E. Wilson, Jeffrey D. Johnson, Constantin Polychronakos () and Michael S. German ()
Additional contact information
Stuart B. Smith: Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA
Hui-Qi Qu: McGill University, Montreal, Québec H3H 1P3, Canada
Nadine Taleb: McGill University, Montreal, Québec H3H 1P3, Canada
Nina Y. Kishimoto: Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA
David W. Scheel: Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA
Yang Lu: McGill University, Montreal, Québec H3H 1P3, Canada
Ann-Marie Patch: Institute of Biomedical and Clinical Science, Peninsula Medical School
Rosemary Grabs: McGill University, Montreal, Québec H3H 1P3, Canada
Juehu Wang: Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA
Francis C. Lynn: Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA
Takeshi Miyatsuka: Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA
John Mitchell: McGill University, Montreal, Québec H3H 1P3, Canada
Rina Seerke: Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA
Julie Désir: Hôpital Erasme-ULB
Serge Vanden Eijnden: Hôpital Erasme-ULB
Marc Abramowicz: Hôpital Erasme-ULB
Nadine Kacet: Hôpital Calmette
Jacques Weill: Hôpital Calmette
Marie-Ève Renard: Hôpital Calmette
Mattia Gentile: Medical Genetic Unit, Di Venere General Hospital
Inger Hansen: Emory University School of Medicine, Atlanta, Georgia 30322, USA
Ken Dewar: McGill University, and Research Institute of the McGill University Health Centre, Montreal, Quebec H3A 1B1, Canada
Andrew T. Hattersley: Institute of Biomedical and Clinical Science, Peninsula Medical School
Rennian Wang: Pharmacology & Medicine, Child Health Research Institute, the University of Western Ontario, London, Ontario N6C 2V5, Canada
Maria E. Wilson: Metabolex Inc., Hayward, California 94545, USA
Jeffrey D. Johnson: Metabolex Inc., Hayward, California 94545, USA
Constantin Polychronakos: McGill University, Montreal, Québec H3H 1P3, Canada
Michael S. German: Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA

Nature, 2010, vol. 463, issue 7282, 775-780

Abstract: Abstract Insulin from the β-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the β-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate β-cells for patients with diabetes.

Date: 2010
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DOI: 10.1038/nature08748

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