Nuclear corepressor and silencing mediator of retinoic and thyroid hormone receptors corepressor expression is incompatible with T3-dependent TRH regulation

Ligand-independent repression by thyroid hormone (T-3) receptors on positive T-3-responsive genes requires corepressor proteins. However, the role of corepressors in regulating genes such as hypothalamic TRH, which are under negative control by T-3, is largely unknown. We examined the expression of mRNAs encoding the corepressors NCoR (nuclear corepressor) and SMRT (silencing mediator of retinoic and thyroid hormone receptors) in the TRH-producing paraventricular nucleus of the mouse hypothalamus. Further, we carried out in vivo functional studies by overexpression. of both corepressors. Three lines of evidence show that NCoR and SMRT expression is incompatible with physiological regulation of TRH. First, Northern blotting revealed TRH and NCoR mRNA expressions to be inversely correlated during postnatal development and as a function of thyroid status. Second, in situ hybridization showed that NCoR and SMRT mRNA expression profiles in the paraventricular nucleus were distinct from that of TRH mRNA. Third, over-expression of full length NCoR and SMRT in the hypothalamus abolished T-3-dependent repression of TRH-luciferase. However, over-expression of NCoR or SMRT did not affect either T-3-independent activation of TRH-luciferase transcription, or transcription from a positively regulated T-3-response element. We conclude that T-3-dependent feedback on TRH expression is unlikely to involve the corepressors NCoR or SMRT.