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BOR - Papers in Press, published online ahead of print October 19, 2005.
Biol Reprod 2005, 10.1095/biolreprod.105.044560
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BIOLOGY OF REPRODUCTION 74, 322–330 (2006)
DOI: 10.1095/biolreprod.105.044560
© 2006 by the Society for the Study of Reproduction, Inc.

Research Article

The Orphan Nuclear Receptor NR4A1 Regulates Insulin-Like 3 Gene Transcription in Leydig Cells1

Nicholas M. Robert 3, Luc J. Martin 3, and Jacques J. Tremblay 2 34 

Ontogeny-Reproduction Research Unit,3 CHUL Research Centre, Ste-Foy, Québec, Canada G1V 4G2 Centre for Research in Biology of Reproduction,4 Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Ste-Foy, Québec, Canada G1K 794

ABSTRACT

Insulin-like 3 (INSL3) is a hormone produced by fetal and adult Leydig cells of the testis and by theca and luteal cells of the adult ovary. In males, INSL3 regulates testicular descent during fetal life, whereas in adults, it acts as a germ cell survival factor. In the ovary, INSL3 regulates oocyte maturation. Despite its importance for male sex differentiation and reproductive function in both sexes, very little is known regarding the molecular mechanisms that regulate Insl3 expression. So far, the nuclear receptor NR5A1 is the only transcription factor known to regulate the mouse Insl3 promoter in Leydig cells. NR5A1 by itself, however, cannot explain the spatiotemporal expression pattern of the Insl3 gene. In the present study, we have identified the orphan nuclear receptor NR4A1 as a novel regulator of INSL3 transcription in Leydig cells. Using RT-PCR, we found that Nr4a1 is coexpressed with Insl3 in purified Leydig cells and in several Leydig cell lines. Through detailed analyses of the mouse and human INSL3 promoter in Leydig cells, we have mapped a novel regulatory element located at –100 bp that is essential and sufficient to confer NR4A1 responsiveness. Consistent with a role for NR4A1 in Insl3 transcription, chromatin immunoprecipitation assays revealed that endogenous NR4A1 binds to the proximal Insl3 promoter in vivo. Finally, we found that NR4A1 is also implicated in cAMP-induced Insl3 transcription in Leydig cells. Taken together, our identification of NR4A1 as an important regulator of mouse and human INSL3 promoter activity helps us to better define the tissue-specific regulation of the INSL3 gene in gonadal cells.

gene regulation, growth factors, Leydig cells, ovary, testis

FOOTNOTES

1 Supported by the Canadian Institutes of Health Research (CIHR) grant number MOP-62752 to J.J.T and a studentship from the Natural Sciences and Engineering Research Council of Canada to L.J.M. J.J.T. is the recipient of a CIHR New Investigator Award.

2 Correspondence: Jacques J. Tremblay, Ontogeny-Reproduction, Room T1–49, CHUL Research Centre, 2705 Laurier Blvd., Ste-Foy, Québec, Canada G1V 4G2. FAX: 418 654 2765; Jacques-J.Tremblay{at}crchul.ulaval.ca




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