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Genes & Dev. 21 (7): 756-769

Copyright © 2007 by Cold Spring Harbor Laboratory Press.

Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4{alpha}

Rana K. Gupta1,3, Nan Gao1,3, Regina K. Gorski1,2, Peter White1, Olga T. Hardy1, Kiran Rafiq1, John E. Brestelli1, Guang Chen2, Christian J. Stoeckert, Jr.1,2,, and Klaus H. Kaestner1,4

1 Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA;
2 Center for Bioinformatics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

Abstract: The failure to expand functional pancreatic beta-cell mass in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing beta-cells is the principle mechanism for beta-cell expansion in adult mice. Here we demonstrate that the proliferative response of beta-cells is dependent on the orphan nuclear receptor hepatocyte nuclear factor-4{alpha} (HNF-4{alpha}), the gene that is mutated in Maturity-Onset Diabetes of the Young 1 (MODY1). Computational analysis of microarray expression profiles from isolated islets of mice lacking HNF-4{alpha} in pancreatic beta-cells reveals that HNF-4{alpha} regulates selected genes in the beta-cell, many of which are involved in proliferation. Using a physiological model of beta-cell expansion, we show that HNF-4{alpha} is required for beta-cell replication and the activation of the Ras/ERK signaling cascade in islets. This phenotype correlates with the down-regulation of suppression of tumorigenicity 5 (ST5) in HNF-4{alpha} mutants, which we identify as a novel regulator of ERK phosphorylation in beta-cells and a direct transcriptional target of HNF-4{alpha} in vivo. Together, these results indicate that HNF-4{alpha} is essential for the physiological expansion of adult beta-cell mass in response to increased metabolic demand.

Key Words: Ras • extracellular regulated kinase • mitogen activated protein kinase • beta-cells • HNF-4{alpha} • type 2 diabetes • gestational diabetes

Received for publication January 26, 2007. Accepted for publication February 9, 2007.


3 These authors contributed equally to this work.

4 Corresponding author.

E-MAIL kaestner{at}mail.med.upenn.edu; FAX (215) 573-5892.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1535507


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