EXPRESSION OF RAT THYROTROPIN-RELEASING-HORMONE (TRH) GENE IN TRH-PRODUCING TISSUES OF TRANSGENIC MICE REQUIRES SEQUENCES LOCATED IN EXON-1

TRH, an amidated tripeptide secreted by certain hypothalamic neurons, is a principal regulator of TSH secretion and thyroid hormone release. TRH is also produced by other neurons in the central nervous system, where it appears to function as a neuromodulator or neurotransmitter, and by certain endocrine cells, where it may act as an autocrine or pa racrine factor. The genomic organization of the rat TRH (rTRH) gene is well understood; however, the domains of the rTRH gene that regulate expression are less well characterized. We observed that the region be tween -47 and +6 of the rTRH gene (relative to the transcription start Site at +1) was active in CA-77 cells, a medullary thyroid carcinoma cell line model of TRH production, but was not active in transgenic mi ce. Inclusion of most of exon 1 (84 out of 103 bp; -47 to +84) increas ed promoter activity in CA-77 cells and was active in transgenic mice, principally in tissues that normally express the TRH gene. Further le ngthening of the 5' end to -243, -547, or -776 retained this expressio n in TRH-producing tissues in transgenic mice, while further increasin g activity in CA-77 cells. These results suggest that cis element(s) l ocated within exon 1 are necessary for the expression of the rTRH gene in vivo.