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J. Biol. Chem., Vol. 280, Issue 19, 19156-19165, May 13, 2005

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Developmental Regulation of Gonadotropin-releasing Hormone Gene Expression by the MSX and DLX Homeodomain Protein Families^*

From the ^aDepartments of Reproductive Medicine and Neuroscience, University of California, San Diego, La Jolla, California 92093-0674, the ^gDepartment of Psychiatry and Langley Porter Psychiatric Institute, University of California, San Francisco, San Francisco, California 9414-0984, and ⁱUnite de Genetique Moleculaire de la Morphogenese, Institut Pasteur, URA 2578 du CNRS, 25 rue du Dr Roux, 75724 Paris Cedex 15, France

Gonadotropin-releasing hormone (GnRH) is the central regulator of the hypothalamic-pituitary-gonadal axis, controlling sexual maturation and fertility in diverse species from fish to humans. GnRH gene expression is limited to a discrete population of neurons that migrate through the nasal region into the hypothalamus during embryonic development. The GnRH regulatory region contains four conserved homeodomain binding sites (ATTA) that are essential for basal promoter activity and cell-specific expression of the GnRH gene. MSX and DLX are members of the Antennapedia class of non-Hox homeodomain transcription factors that regulate gene expression and influence development of the craniofacial structures and anterior forebrain. Here, we report that expression patterns of the Msx and Dlx families of homeodomain transcription factors largely coincide with the migratory route of GnRH neurons and co-express with GnRH in neurons during embryonic development. In addition, MSX and DLX family members bind directly to the ATTA consensus sequences and regulate transcriptional activity of the GnRH promoter. Finally, mice lacking MSX1 or DLX1 and 2 show altered numbers of GnRH-expressing cells in regions where these factors likely function. These findings strongly support a role for MSX and DLX in contributing to spatiotemporal regulation of GnRH transcription during development.

Received for publication, February 22, 2005

^* This work was supported 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 Supported in part by National Institutes of Health Training Grant T32 DA07315. Present address: Emory University, Rollins School of Public Health, 1518 Clifton Road, Atlanta, GA 30322.

^c Supported in part by a Lalor Foundation postdoctoral fellowship. Present address: Dept. of Biotech. and Food Engineering, Technion, Haifa 32000, Israel.

^d Supported in part by a Howell Foundation research fellowship.

^e Supported in part by a Lalor Foundation postdoctoral fellowship. Present address: Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, 37 Convent Dr., Bldg. 37, Rm. 3E-24, Bethesda, MD 20892.

^f Supported in part by National Institutes of Health Training Grant T32 DA07315.

^h These authors contributed equally to this work.

^j 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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