Foxa2 Controls Pdx1 Gene Expression in Pancreatic β-Cells In Vivo
- Catherine S. Lee13,
- Newman J. Sund13,
- Marko Z. Vatamaniuk23,
- Franz M. Matschinsky23,
- Doris A. Stoffers34 and
- Klaus H. Kaestner13
- 1Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
- 2Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
- 3Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
- 4Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Abstract
Differentiation of early foregut endoderm into pancreatic endocrine and exocrine cells depends on a cascade of gene activation events controlled by various transcription factors. Prior in vitro analysis has suggested that the forkhead/winged helix transcription factor Foxa2 (formerly HNF-3β) is a major upstream regulator of Pdx1, a homeobox gene essential for pancreatic development. Pdx1 is also essential for the maintenance of glucose homeostasis, as its human orthologue, IPF-1, is mutated in a subset of patients with early-onset type 2 diabetes (MODY4). To analyze the Foxa2/Pdx1 regulatory cascade during pancreatic β-cell differentiation, we used conditional gene ablation of Foxa2 in mice. We demonstrated that the deletion of Foxa2 in β-cell−specific knockout mice results in downregulation of Pdx1 mRNA and subsequent reduction of PDX-1 protein levels in islets. These data represent the first in vivo demonstration that Foxa2 acts upstream of Pdx1 in the differentiated β-cell.
Footnotes
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Address correspondence and reprint requests to Dr. Klaus H. Kaestner, Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia, PA 19104-6145. E-mail: kaestner{at}mail.med.upenn.edu.
Received for publication 16 January 2002 and accepted in revised form 6 May 2002.
C.S.L. and N.J.S. contributed equally to this article.
Hprt, hypoxanthine-phosphoribosyltransferase; IPF-1, insulin promoter factor 1; Pn, postnatal day n; PBT, PBS containing 0.1% BSA and 0.2% Triton X-100; p.c., post coitum; PP, pancreatic polypeptide.
- DIABETES
