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Feedback on Hypothalamic TRH Transcription Is Dependent on Thyroid Hormone Receptor N Terminus

Laboratoire de Physiologie Générale et Comparée (H.G., S.M.D., N.B., I.S., B.A.D.), Unité Mixte de Recherche 8572, Centre Nationale de la Recherche Scientifique, Muséum National d’Histoire Naturelle, 75231 Paris, cedex 5, France; and Institut de Biologie Animale (E.J., B.D.), Universite de Lausanne, Batiment de Biologie, CH-1015 Lausanne, Switzerland

Address all correspondence and requests for reprints to: Dr. Barbara Demeneix, Laboratoire de Physiologie Generale et Comparee Museum National d’Histoire Naturelle, Unité Mixte de Recherche 8572, Centre Nationale de la Recherche Scientifique, 75231, Paris cedex 5, France. E-mail: demeneix{at}mnhn.fr.

The ß thyroid hormone receptor (TRß), but not TR1, plays a specific role in mediating T₃-dependent repression of hypothalamic TRH transcription. To investigate the structural basis of isoform specificity, we compared the transcriptional regulation and DNA binding obtained with chimeric and N-terminally deleted TRs. Using in vivo transfection assays to follow hypothalamic TRH transcription in the mouse brain, we found that TRß1 and chimeras with the TRß1 N terminus did not affect either transcriptional activation or repression from the rat TRH promoter, whereas N-terminally deleted TRß1 impaired T₃-dependent repression. TR1 or chimeras with the TR1 N terminus reduced T₃-independent transcriptional activation and blocked T₃-dependent repression of transcription. Full deletion of the TR1 N terminus restored ligand-independent activation of transcription. No TR isoform specificity was seen after transcription from a positive thyroid hormone response element. Gel mobility assays showed that all TRs tested bound specifically to the main negative thyroid hormone response element in the TRH promoter (site 4). Addition of neither steroid receptor coactivator 1 nor nuclear extracts from the hypothalamic paraventricular nuclei revealed any TR isoform specificity in binding to site 4. Thus N-terminal sequences specify TR T₃-dependent repression of TRH transcription but not DNA recognition, emphasizing as yet unknown neuron-specific contributions to protein-promoter interactions in vivo.

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