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

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.

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