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Departments of Reproductive Medicine and Neuroscience University of California, San Diego La Jolla, California 92093-0674
Neuroendocrine control of the reproductive cascade is mediated by GnRH, which in mammals is produced by a subset of neurons scattered throughout the hypothalamus and forebrain. Utilizing a cultured cell model of GnRH neurons (GT1–7 cells), two regulatory regions in the rat GnRH 5' flanking DNA were identified as essential for cell-type specificity: a 300-bp enhancer and a 173-bp conserved proximal promoter. Using transient transfections to compare expression in GT1–7 cells to a non-GnRH-expressing cell type (NIH 3T3), we show that the GnRH enhancer and the proximal promoter each play roles in conferring this specificity. Deletion of footprint 2 (FP2; -26 to -76) from the promoter when coupled to the GnRH enhancer diminishes reporter activity in GT1–7 cells more strongly than in NIH 3T3 cells. Furthermore, deletion of FP2 from the promoter when coupled to the heterologous Rous sarcoma virus 5'-long terminal repeat promoter abolishes the difference in reporter activity between GT1–7 and NIH 3T3 cells, suggesting that FP2 of the GnRH promoter is necessary for cell-specific expression. In addition, FP2 alone is sufficient to confer cell-specific expression and can interact with the GnRH enhancer to augment reporter gene expression specifically in GT1–7 cells. Finally, a 31-bp sequence from within FP2 (-63 to -33) synergistically activates transcription when coupled with the GnRH enhancer in GT1–7 cells but not in NIH 3T3 cells. Thus, this 31-bp region contains elements necessary for interaction between the GnRH enhancer and promoter. We show that two of five protein complexes that bind to the -63 to -33 region are GT1–7 cell specific, and both of them appear to be homeodomain proteins. The identification of a cell-specific element in the GnRH proximal promoter significantly advances our understanding of the transcriptional basis for neuron-specific GnRH gene expression.
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