Rfx6 directs islet formation and insulin production in mice and humans

Authors

Stuart B. Smith, University of California, San Francisco
Hui Qi Qu, Université McGill
Nadine Taleb, Université McGill
Nina Y. Kishimoto, University of California, San Francisco
David W. Scheel, University of California, San Francisco
Yang Lu, Université McGill
Ann Marie Patch, Peninsula Medical School, Universities of Exeter and Plymouth
Rosemary Grabs, Université McGill
Juehu Wang, University of California, San Francisco
Francis C. Lynn, University of California, San Francisco
Takeshi Miyatsuka, University of California, San Francisco
John Mitchell, Université McGill
Rina Seerke, University of California, San Francisco
Julie Désir, Hôpital Erasme
Serge Vanden Eijnden, Hôpital Erasme
Marc Abramowicz, Hôpital Erasme
Nadine Kacet, CHU Lille
Jacques Weill, CHU Lille
Marie Éve Renard, CHU Lille
Mattia Gentile, Di Venere Teaching Hospital
Inger Hansen, Emory University School of Medicine
Ken Dewar, Centre Universitaire de Santé McGill
Andrew T. Hattersley, Peninsula Medical School, Universities of Exeter and Plymouth
Rennian Wang, Western UniversityFollow
Maria E. Wilson, Metabolex, Inc.
Jeffrey D. Johnson, Metabolex, Inc.

Document Type

Article

Publication Date

2-11-2010

Journal

Nature

Volume

463

Issue

7282

First Page

775

Last Page

780

URL with Digital Object Identifier

10.1038/nature08748

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. © 2010 Macmillan Publishers Limited. All rights reserved.