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Nuclear Corepressor and Silencing Mediator of Retinoic and Thyroid Hormone Receptors Corepressor Expression Is Incompatible with T₃-Dependent TRH Regulation

Laboratoire de Physiologie Générale et Comparée, Muséum National d’Histoire Naturelle, Centre National de la Recherche Scientifique UMR 8572, 75231 Paris Cedex 5, France

Address all correspondence and requests for reprints to: Dr. Barbara A. Demeneix, Laboratoire de Physiologie Générale et Comparée, Muséum National d’Histoire Naturelle, UMR Centre National de la Recherche Scientifique 8572, 7 rue Cuvier, 75231 Paris, Cedex 5, France. E-mail: demeneix{at}mnhn.fr

Ligand-independent repression by thyroid hormone (T₃) receptors on positive T₃-responsive genes requires corepressor proteins. However, the role of corepressors in regulating genes such as hypothalamic TRH, which are under negative control by T₃, 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 T₃-dependent repression of TRH-luciferase. However, over-expression of NCoR or SMRT did not affect either T₃-independent activation of TRH-luciferase transcription, or transcription from a positively regulated T₃-response element. We conclude that T₃ -dependent feedback on TRH expression is unlikely to involve the corepressors NCoR or SMRT.

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