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Molecular and Cellular Biology, October 2003, p. 6713-6724, Vol. 23, No. 19
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.19.6713-6724.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Pancreatic-Duodenal Homeobox 1 Regulates Expression of Liver Receptor Homolog 1 during Pancreas Development

Jean-Sébastien Annicotte,1 Elisabeth Fayard,1 Galvin H. Swift,2 Lars Selander,3 Helena Edlund,3 Toshiya Tanaka,4 Tatsuhiko Kodama,4 Kristina Schoonjans,1 and Johan Auwerx1,5*

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP 67404,1 Institut Clinique de la Souris, Illkirch, CU de Strasbourg, Strasbourg, France,5 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148,2 Umeå Center for Molecular Medicine, University of Umeå, SE-901 87 Umeå, Sweden,3 Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, Tokyo University, Tokyo 153-8904, Japan4

Received 4 February 2003/ Returned for modification 10 March 2003/ Accepted 25 June 2003

Liver receptor homolog 1 (LRH-1) and pancreatic-duodenal homeobox 1 (PDX-1) are coexpressed in the pancreas during mouse embryonic development. Analysis of the regulatory region of the human LRH-1 gene demonstrated the presence of three functional binding sites for PDX-1. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis showed that PDX-1 bound to the LRH-1 promoter, both in cultured cells in vitro and during pancreatic development in vivo. Retroviral expression of PDX-1 in pancreatic cells induced the transcription of LRH-1, whereas reduced PDX-1 levels by RNA interference attenuated its expression. Consistent with direct regulation of LRH-1 expression by PDX-1, PDX-1-/- mice expressed smaller amounts of LRH-1 mRNA in the embryonic pancreas. Taken together, our data indicate that PDX-1 controls LRH-1 expression and identify LRH-1 as a novel downstream target in the PDX-1 regulatory cascade governing pancreatic development, differentiation, and function.

* Corresponding author. Mailing address: Institut de Génétique et de Biologie Moléculaire et Cellulaire, ICS, BP 10142, 67404 Illkirch, France. Phone: 33 388 65 32 01. Fax: 33 388 65 32 01. E-mail: auwerx{at}igbmc.u-strasbg.fr.

Molecular and Cellular Biology, October 2003, p. 6713-6724, Vol. 23, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.19.6713-6724.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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