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The Otx2 Homeoprotein Regulates Expression from the Gonadotropin-Releasing Hormone Proximal Promoter

Departments of Reproductive Medicine and Neuroscience and the Center for Molecular Genetics (C.G.K., M.E.C., P.L.M.) University of California, San Diego La Jolla, California 92093-0674
Dipartmento di Biologia e Tecnologia Istituto Scientifico H. S. Raffaele (G.L., E.B.) 20132 Milano, Italy
Centro per lo studio della Farmacologia Cellulare e Molecolare (E.B.) Consiglio Nazionale delle Ricerche 20129 Milano, Italy

The GnRH gene is expressed exclusively in a highly restricted population of approximately 800 neurons in the mediobasal hypothalamus in the mouse. The Otx2 homeoprotein has been shown to colocalize with GnRH in embryonic mouse brain. We have identified a highly conserved bicoid-related Otx target sequence within the proximal promoter region of the GnRH gene from several species. This element from the rat GnRH promoter binds baculovirus-expressed Otx2 protein and Otx2 protein in nuclear extracts of a hypothalamic GnRH-expressing neuronal cell line, GT1–7. Transient transfection assays indicate that the GnRH promoter Otx/bicoid site is required for specific expression of the GnRH gene in GT1–7 cells and that it can confer specificity to a neutral Rous sarcoma virus (RSV) promoter in GT1–7 cells but not in NIH3T3 cells. Overexpression of mouse Otx2 in GT1–7 cells induces expression of a GnRH promoter plasmid, an effect that is dependent upon the Otx binding site. Thus, the GnRH proximal promoter is regulated by the Otx2 homeoprotein. Finally, we have now demonstrated the presence of Otx2 protein in the GnRH neurons of the adult mouse hypothalamus. These data suggest that Otx2 is important in the development of the GnRH neuron and/or in the maintenance of GnRH expression in the adult mouse hypothalamus.

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