REPRESSION OF GONADOTROPIN-RELEASING-HORMONE PROMOTER ACTIVITY BY THEPOU HOMEODOMAIN TRANSCRIPTION FACTOR SCIP OCT-6/TST-1 - A REGULATORY MECHANISM OF PHENOTYPE EXPRESSION/

POU domain transcription factors are required for neuropeptide express ion in selected subsets of hypothalamic neuroendocrine neurons. We now report that expression of the gonadotropin-releasing hormone (GnRH) g ene, which controls sexual development, is regulated by the POU protei n SCIP/Oct-6/Tst-1. Reverse transcriptase PCR cloning and RNase protec tion assays demonstrated the presence of SCIP/Oct-6/Tst-1 mRNA in the GnRH-producing neuronal cell line GT1-7. The physiological relevance o f this regulatory activity was suggested by the detection of SCIP/Oct- 6/Tst-1 mRNA in a subset of GnRH neurons in the hypothalamus of prepub ertal female rats. Coexpression of SCIP/Oct-6/Tst-1 in neuronal cells inhibited rat GnRH (rGnRH) promoter activity via three regions of the proximal rGnRH promoter containing SCIP/Oct-6/Tst-1 binding sites. DNa se I footprinting, gel shift assays, and DNA and protein mutagenesis s tudies indicated that both direct DNA binding and protein-protein inte ractions are required for SCIP/Oct-6/Tst-1 modulation of GnRH gene exp ression. Activation of SCIP/Oct-6/Tst-1 expression in terminally diffe rentiated GnRH neurons may be a factor determining the ratio of phenot ypically ''inactive'' versus ''active'' GnRH neurons during postnatal life.