Winter Harald, Braig Claudia, Zimmermann Ulrike, Geisler Hyun-Soon, Fränzer Jürgen-Theodor, Weber Thomas, Ley Matthias, Engel Jutta, Knirsch Martina, Bauer Karl, Christ Stephanie, Walsh Edward J, McGee JoAnn, Köpschall Iris, Rohbock Karin, Knipper Marlies
Department of Otolaryngology, Tübingen Hearing Research Centre (THRC), Laboratory of Molecular Neurobiology, University of Tübingen, Elfriede-Aulhorn-Strasse 5, 72076 Tübingen, Germany.
J Cell Sci. 2006 Jul 15;119(Pt 14):2975-84. doi: 10.1242/jcs.03013. Epub 2006 Jun 27.
Thyroid hormone (TH or T3) and TH-receptor beta (TRbeta) have been reported to be relevant for cochlear development and hearing function. Mutations in the TRbeta gene result in deafness associated with resistance to TH syndrome. The effect of TRalpha1 on neither hearing function nor cochlear T3 target genes has been described to date. It is also uncertain whether TRalpha1 and TRbeta 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 TRbeta. Simultaneously Kcnq4 expression was activated in the same cells by derepression of TRalpha1 aporeceptors mediated by an identified THresponse 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 TRalpha1 in final cell differentiation.
甲状腺激素（TH或T3）和甲状腺激素受体β（TRβ）已被报道与耳蜗发育和听力功能相关。TRβ基因突变会导致与甲状腺激素抵抗综合征相关的耳聋。迄今为止，尚未描述TRα1对听力功能或耳蜗T3靶基因的影响。TRα1和TRβ是否能在单个细胞内同时作用于不同的靶基因也尚不确定。我们聚焦于两个同时表达的外毛细胞基因，钾通道Kcnq4和运动蛋白prestin Slc26a5。在外毛细胞中，TH通过TRβ增强了prestin基因的表达。同时，通过由一个已确定的甲状腺激素反应元件介导的TRα1无配体受体的去抑制作用，Kcnq4在同一细胞中的表达被激活，该反应元件调节KCNQ4启动子活性。我们表明，T3靶基因在单个细胞内对具有配体结合（全受体）或未结合（无配体受体）的甲状腺激素受体的敏感性可能不同，并提示TRα1在最终细胞分化中发挥作用。
