Physiological regulation of hypothalamic TRH transcription in vivo is T3 receptor isoform specific

Thyroid hormone (tri-iodo-thyronine, T-3) exerts transcriptional effects on target genes in responsive cells. These effects are determined by DNA/protein interactions governed by the type of T-3 receptors (TRs) in the cell. As TRs show tissue and developmental variations, regulation is best addressed in an integrated in vivo model. We examined TR subtype effects on thyrotropin-releasing hormone (TRH) transcription and on the pituitary/thyroid axis end point: thyroid hormone secretion. Polyethylenimine sewed to transfect a TRH-luciferase construct containing 554 bp of the rat TRH promoter into the hypothalami of newborn mice. Transcription from the TRH promoter was regulated in a physiologically faithful manner, being significantly increased in hypothyroidism and decreased in T-3-treated animals. Moreover, when various ligand binding forms of mouse or chicken TR beta and TR alpha were expressed with TRH-luciferase, all forms of TR beta gave T-3-dependent regulation of TRH transcription, whereas transcription was T-3 insensitive with each TR alpha tested. Moreover, chicken TR alpha increased TRH transcription sixfold, whereas mouse TR alpha decreased transcription. These transcriptional effects had correlated physiological consequences: expression of the chicken TR alpha in the hypothalamus of newborn mice raised circulating T-4 levels by fourfold, whereas mouse TR alpha had opposite effects. Thus, TR subtypes have distinct, physiologically relevant effects on TRH transcription.