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

The β thyroid hormone receptor (TRβ), but not TRα1, 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 TRβ1 and chimeras with the TRβ1 N terminus did not affect either transcriptional activation or repression from the rat TRH promoter, whereas N-terminally deleted TRβ1 impaired T3-dependent repression. TRα1 or chimeras with the TRα1 N terminus reduced T3-independent transcriptional activation and blocked T3-dependent repression of transcription. Full deletion of the TRα1 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 ...