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J. Biol. Chem., Vol. 279, Issue 29, 30287-30297, July 16, 2004

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TALE Homeodomain Proteins Regulate Gonadotropin-releasing Hormone Gene Expression Independently and via Interactions with Oct-1^*

From the Departments of ^aReproductive Medicine, ^jNeurosciences, and ⁱPathology, School of Medicine, University of California, San Diego, La Jolla, California 92903

Gonadotropin-releasing hormone (GnRH) is the central regulator of reproductive function. Expression of the GnRH gene is confined to a rare population of neurons scattered throughout the hypothalamus. Restricted expression of the rat GnRH gene is driven by a multicomponent enhancer and an evolutionarily conserved promoter. Oct-1, a ubiquitous POU homeodomain transcription factor, was identified as an essential factor regulating GnRH transcription in the GT1-7 hypothalamic neuronal cell line. In this study, we conducted a two-hybrid interaction screen in yeast using a GT1-7 cDNA library to search for specific Oct-1 cofactors. Using this approach, we isolated Pbx1b, a TALE homeodomain transcription factor that specifically associates with Oct-1. We show that heterodimers containing Pbx/Prep1 or Pbx/Meis1 TALE homeodomain proteins bind to four functional elements within the GnRH regulatory region, each in close proximity to an Oct-1-binding site. Cotransfection experiments indicate that TALE proteins are essential for GnRH promoter activity in the GT1-7 cells. Moreover, Pbx1 and Oct-1, as well as Prep1 and Oct-1, form functional complexes that enhance GnRH gene expression. Finally, Pbx1 is expressed in GnRH neurons in embryonic as well as mature mice, suggesting that the associations between TALE homeodomain proteins and Oct-1 regulate neuron-specific expression of the GnRH gene in vivo.

Received for publication, March 17, 2004 , and in revised form, May 10, 2004.

^* 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.

^b Fellow of the Lalor Foundation.

^c Both authors contributed equally to this work.

^d Supported in part by National Institutes of Health Training Grant DA07315.

^e Supported in part by National Institutes of Health Training Grant T32 AG00216. Present address: Dept. of Development and Cell Biology, University of California, 4150 McGaugh Hall, Irvine, CA 92697-2300.

^f Present address: Dept. of Chemistry and Biochemistry, UCLA, 607 Charles E. Young Dr. E., Los Angeles, CA 90095-1569.

^g Supported by National Institutes of Health Grant F32 HD41301 and the Lalor Foundation.

^h Recipient of an American Cancer Society fellowship. Present address: Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Dr., San Diego, CA 92121.

^k 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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