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J. Biol. Chem., Vol. 280, Issue 35, 30975-30983, September 2, 2005

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The Groucho-related Gene Family Regulates the Gonadotropin-releasing Hormone Gene through Interaction with the Homeodomain Proteins MSX1 and OCT1^*

Naama Rave-Harel, Nichol L. G. Miller¶||, Marjory L. Givens||**, and Pamela L. Mellon

From the Departments of Reproductive Medicine and Neurosciences, University of California, San Diego, La Jolla, California, 92093-0674

Gonadotropin-releasing hormone (GnRH) is exclusively expressed in a unique population of hypothalamic neurons that controls reproductive function. GnRH gene expression is highly dynamic. Its transcriptional activity is regulated in a complex spatiotemporal manner during embryonic development and postnatal life. Although a variety of transcription factors have been identified as regulators of GnRH transcription, most are promiscuous in their DNA-binding requirements, and none are solely expressed in GnRH neurons. Their specific activity is probably determined by interactions with distinct cofactors. Here we find that the Groucho-related gene (GRG) family of co-repressors is expressed in a model cell line for the GnRH neuron and co-expresses with GnRH during prenatal development. GRG proteins associate in vivo with the GnRH promoter. Furthermore, GRG proteins interact with two regulators of GnRH transcription, the homeodomain proteins MSX1 and OCT1. Co-transfection experiments indicate that GRG proteins regulate GnRH promoter activity. The long GRG forms enhance MSX1 repression and counteract OCT1 activation of the GnRH gene. In contrast, the short form, GRG5, has a dominant-negative effect on MSX1-dependent repression. Taken together, these data suggest that the dynamic switch between activation and repression of GnRH transcription is mediated by recruitment of the GRG co-regulators.

Received for publication, March 1, 2005 , and in revised form, July 5, 2005.

^* This work was supported in part by National Institutes of Health Grant R01 DK44838 (to P. L. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Lalor Foundation. Present address: Dept. of Biotechnology and Food Engineering, Technion, Haifa 32000, Israel.

^¶ Supported in part by National Institutes of Health Grant GM08666.

^|| These two authors contributed equally to this work.

^** Supported in part by National Institutes of Health Grant DA07315. Present address: Emory University, School of Public Health, 1518 Clifton Rd., Atlanta, GA 30322.

To whom correspondence should be addressed: Dept. of Reproductive Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0674. Tel.: 858-534-1312; Fax: 858-534-1438; E-mail: pmellon{at}ucsd.edu.

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