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Neuron-Specific Expression in Vivo by Defined Transcription Regulatory Elements of the GnRH Gene

Departments of Reproductive Medicine (M.A.L., B.T.P., S.B.N., P.L.M.) and Neuroscience (L.A.M., J.K., P.L.M.) and Center for the Study of Reproductive Biology and Disease (M.A.L., P.L.M.), University of California-San Diego, La Jolla, California 92093-0674

Address all correspondence and requests for reprints to: Dr. Mark A. Lawson, Department of Reproductive Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, California 92093-0674. E-mail: . mlawson{at}ucsd.edu

The GnRH-expressing neurons are the ultimate regulator of reproductive function. GnRH gene expression is limited to this small population of neurons in the hypothalamus. Transfections using 3 kb of the rat or mouse 5'-regulatory region provide specific gene expression in the hypothalamic cell line GT1-7. The combination of two elements, a 300-bp enhancer and a 173-bp promoter, recapitulates specificity in GT1-7 cells. It was not known whether these elements could specifically target gene expression throughout development in the whole animal. We demonstrate that the 3-kb rat GnRH regulatory region provides a higher degree of specificity than the equivalent mouse sequence in a mouse hypothalamic cell line. Moreover, combination of the enhancer and the promoter of the rat gene targets expression to GnRH neurons in transgenic mice in a developmentally appropriate manner. Transgene expression is regulated by activin A, a known activator of GnRH gene expression. In contrast, the enhancer on a heterologous promoter produces inappropriate expression in vivo. We conclude that the enhancer and promoter regions of the rat GnRH gene are necessary for targeted expression to hypothalamic neurons and are sufficient to confer regulated, cell type-specific expression to a reporter gene in vivo.

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