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Molecular and Cellular Biology, August 2006, p. 6037-6046, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.02445-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1{alpha} Are Required for Time-Specific Gene Expression during Liver Development

Jean-Bernard Beaudry,1 Christophe E. Pierreux,1 Graham P. Hayhurst,2 Nicolas Plumb-Rudewiez,1 Mary C. Weiss,2 Guy G. Rousseau,1 and Frédéric P. Lemaigre1*

Hormone and Metabolic Research Unit, Institute of Cellular Pathology and Université Catholique de Louvain, 75 Avenue Hippocrate, B-1200 Brussels, Belgium,1 Département de Biologie du Développement, Institut Pasteur, Rue du Dr. Roux 25, 75724 Paris Cedex 15, France2

Received 22 December 2005/ Returned for modification 7 February 2006/ Accepted 25 May 2006

During liver development, hepatocytes undergo a maturation process that leads to the fully differentiated state. This relies at least in part on the coordinated action of liver-enriched transcription factors (LETFs), but little is known about the dynamics of this coordination. In this context we investigate here the role of the LETF hepatocyte nuclear factor 6 (HNF-6; also called Onecut-1) during hepatocyte differentiation. We show that HNF-6 knockout mouse fetuses have delayed expression of glucose-6-phosphatase (g6pc), which catalyzes the final step of gluconeogenesis and is a late marker of hepatocyte maturation. Using a combination of in vivo and in vitro gain- and loss-of-function approaches, we demonstrate that HNF-6 stimulates endogenous g6pc gene expression directly via a synergistic and interdependent action with HNF-4 and that it involves coordinate recruitment of the coactivator PGC-1{alpha}. The expression of HNF-6, HNF-4, and PGC-1{alpha} rises steadily during liver development and precedes that of g6pc. We provide evidence that threshold levels of HNF-6 are required to allow synergism between HNF-6, HNF-4, and PGC-1{alpha} to induce time-specific expression of g6pc. Our observations on the regulation of g6pc by HNF-6 provide a model whereby synergism, interdependency, and threshold concentrations of LETFs and coactivators determine time-specific expression of genes during liver development.

* Corresponding author. Mailing address: Box 7529, 75 Avenue Hippocrate, B-1200 Brussels, Belgium. Phone: 32 2 764 7583. Fax: 32 2 764 7507. E-mail: lemaigre{at}horm.ucl.ac.be.

Molecular and Cellular Biology, August 2006, p. 6037-6046, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.02445-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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