Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide that plays a key role in the initiation of normal puberty. In children, pathologic processes such as CNS tumors or CNS trauma may accelerate this process resulting in precocious puberty. The mechanisms involved in the induction of GnRH secretion are still unclear, but may involve the binding of growth factors (TGF-α), secreted by glial cells at the lesion site, to EGF receptors on GnRH neurons. A GnRH-expressing neuronal cell line (Gn11) was derived from a CNS tumor in transgenic mice bearing a human GnRH (hGnRH) 5' flanking DNA -SV40 T antigen transgene. An RNAse protection assay on cells cultured in 10% serum confirmed the presence of GnRH mRNA. We demonstrated that the consensus AP-1 site (TGACTCA) in the hGnRH gene (-402/-396 bp) binds a purified recombinant human c-jun protein and a phorbol ester(TPA) inducible protein from GN11 cells. TPA exposure increased the transcriptional activity of stable clones of GN11 cells containing 5' hGnRH-Luciferase fusion constructs. The increased luciferase expression mapped to the AP-1 site, and was preceded by an increase in c-jun and c-fos mRNA, indicating that stimulation of GnRH-Luciferase expression is mediated by increased AP-1(c-jun/c-fos) activity. Exposure to TGF-α also increased GnRH-Luciferase expression by acting through EGF receptors present on GnRH neurons. Thus, CNS lesions which release TGF-α may induce precocious puberty by increasing GnRH transcription via a signalling mechanism involving AP-1 activation. Inhibitors of this pathway may provide future therapeutic modalities for precocious puberty.