TTF-1, a homeodomain gene required for diencephalic morphogenesis, is postnatally expressed in the neuroendocrine brain in a developmentally regulated and cell-specific fashion

TTF-1 is a member of the Nkx family of homeodomain genes required for morph ogenesis of the hypothalamus. Whether TTF-1, or other Nkx genes, contribute s to regulating differentiated hypothalamic functions is not known. We now report that postnatal hypothalamic TTF-1 expression is developmentally regu lated and associated with the neuroendocrine process of female sexual devel opment. Lesions of the hypothalamus that cause sexual precocity transiently activate neuronal TTF-1 expression near the lesion site. In intact animals , hypothalamic TTF-1 mRNA content also increases transiently, preceding the initiation of puberty. Postnatal expression of the TTF-1 gene was limited to subsets of hypothalamic neurons, including LHRH neurons, which control s exual maturation, and preproenkephalinergic neurons of the lateroventromedi al nucleus of the basal hypothalamus, which restrain sexual maturation and facilitate reproductive behavior. TTF-1 mRNA was also detected in astrocyte s of the median eminence and ependymal/subependymal cells of the third vent ricle, where it colocalized with erbB-2, a receptor involved in facilitatin g sexual development. TTF-1 binds to and transactivates the erbB-2 and LHRH promoters, but represses transcription of the preproenkephalin gene. The s ingular increase in hypothalamic TTF-1 gene expression that precedes the in itiation of puberty, its highly specific pattern of cellular expression, an d its transcriptional actions on genes directly involved in neuroendocrine reproductive regulation suggest that TTF-1 may represent one of the control ling factors that set in motion early events underlying the central activat ion of mammalian puberty.