Thyroid hormone receptors TRα1 and TRβ differentially regulate gene expression of Kcnq4 and prestin during final differentiation of outer hair cells

Thyroid hormone (TH or T3) and TH-receptor beta (TR beta) have been reported to be relevant for cochlear development and hearing function. Mutations in the TR beta gene result in deafness associated with resistance to TH syndrome. The effect of TR alpha 1 on neither hearing function nor cochlear T3 target genes has been described to date. It is also uncertain whether TR alpha 1 and TR beta can act simultaneously on different target genes within a single cell. We focused on two concomitantly expressed outer hair cell genes, the potassium channel Kcnq4 and the motor protein prestin Slc26a5. In outer hair cells, TH enhanced the expression of the prestin gene through TR beta. Simultaneously Kcnq4 expression was activated in the same cells by derepression of TR alpha 1 aporeceptors mediated by an identified TH-response element, which modulates KCNQ4 promoter activity. We show that T3 target genes can differ in their sensitivity to TH receptors having the ligand either bound (holoreceptors) or not bound (aporeceptors) within single cells, and suggest a role for TR alpha 1 in final cell differentiation.