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Identification of a Discrete Promoter Region of the Human GnRH Gene That Is Sufficient for Directing Neuron-Specific Expression: A Role for POU Homeodomain Transcription Factors

Department of Pediatrics (A.W., H.H.K., S.R.), University of Chicago, Chicago, Illinois 60637; The Shriver Center (S.T.), Waltham, Massachusetts 02452; and Department of Medicine (D.E.J.S.), Children’s Hospital, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Dr. Andrew Wolfe, The University of Chicago, Department of Pediatrics, 5839 South Maryland Avenue MC5053, Chicago, Illinois 60637. E-mail: awolfe{at}peds.bsd.uchicago.edu.

The human GnRH (hGnRH) gene is expressed, and the GnRH decapeptide produced, primarily in the GnRH neurons of the diencephalon. The molecular elements important for the cell-specific expression and regulation of the hGnRH gene are not well established at this time; therefore, we have used a transgenic mouse model to isolate cis-regulatory elements important for directing gene expression to GnRH neurons in the hypothalamus. Gene constructs consisting of various promoter deletion fragments of the hGnRH gene fused to the luciferase (LUC) reporter gene have been used to create transgenic mouse lines. Cell-specific expression, with the criterion being luciferase expression directed to GnRH neurons of the hypothalamus, was observed when 992 bp, but not 795 bp, of the hGnRH gene promoter were used. Tissue-specific expression was also observed when a deletion construct containing the region from -992 to -763 was fused to a minimal 48-bp promoter fragment fused to LUC. These data indicate that the region between -992 and -795 contains elements both essential and sufficient for targeting gene expression to GnRH neurons. This promoter region was found to contain two DNA-binding sites for the POU class of transcription factors, each of which specifically interacted with the POU homeodomain proteins Brn-2 and Oct-1. Functional studies demonstrated that Brn-2 increased promoter activity of the human and mouse GnRH genes.

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