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Expansion of adult -cell mass in response to increased metabolic demand is dependent on HNF-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

The failure to expand functional pancreatic -cell mass in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing -cells is the principle mechanism for -cell expansion in adult mice. Here we demonstrate that the proliferative response of -cells is dependent on the orphan nuclear receptor hepatocyte nuclear factor-4 (HNF-4), 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 in pancreatic -cells reveals that HNF-4 regulates selected genes in the -cell, many of which are involved in proliferation. Using a physiological model of -cell expansion, we show that HNF-4 is required for -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 mutants, which we identify as a novel regulator of ERK phosphorylation in -cells and a direct transcriptional target of HNF-4 in vivo. Together, these results indicate that HNF-4 is essential for the physiological expansion of adult -cell mass in response to increased metabolic demand.

[Keywords: Ras; extracellular regulated kinase; mitogen activated protein kinase; -cells; HNF-4; type 2 diabetes; gestational diabetes]

Received January 26, 2007; revised version accepted February 9, 2007.

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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