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

Abstract

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.

ACKNOWLEDGMENTS

We thank Lluis Fajas for helpful discussions and Céline Haby, Thomas Ding, Estelle Heitz, Stéphanie Miard, and Maryam Rastegar for excellent technical assistance.

This work was supported by grants from the Centre Nationale de Recherche Scientifique (CNRS), the Institut National pour la Santé et la Recherche Médicale (INSERM), Hopitaux Universitaires de Strasbourg, European Union (QLG1-CT-1999-00674 and QLRT-2001-00930), and NIH (1-P01-DK59820-01). J.S.A. and E.F. are supported by fellowships from the Ligue Nationale Contre le Cancer and the Association pour la Recherche sur le Cancer, respectively.