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首页> 外文期刊>Cellular Physiology and Biochemistry >Complete activation of thyroid hormone receptor β by T _3 is essential for normal cochlear function and morphology in mice
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Complete activation of thyroid hormone receptor β by T _3 is essential for normal cochlear function and morphology in mice

机译：T _3完全激活甲状腺激素受体β对于小鼠正常的耳蜗功能和形态至关重要

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摘要

Thyroid hormones (THs) regulate many developmental processes, including the developmental onset of cochlear differentiation and function. TH action is mediated mostly by triiodothyronine (T3) bound to thyroid hormone nuclear receptors (TRs). At positive regulated genes and in the absence of THs, nuclear co-repressors are bound to TRs and decrease basal transcription rate. Ligand (T _3) binding results in the dissociation of co-repressors and the recruitment of co-activators to the complex, which results in full transcriptional activation. Methods: We measured cochlear function in two knock-in mouse models: TRβ ~(E457A/E457A), with the TRβ co-activator binding surface (AF-2) disrupted to prevent co-activator binding; and TRβ ~(Δ337T/Δ337T), which is unable to bind T _3. Cochlear morphology and function were analyzed in 10-week-old normal and mutated mice. Cochlear function was determined by measuring auditory brainstem responses, cochlear tuning and compound action potential (CAP) thresholds. Results: All TRβ ~(Δ337T/Δ337T) and 85% of the TRβ ~(E457A/E457A) mice presented elevated CAP thresholds (P < 0.05 or less). Five percent of the TRβ ~(E457A/E457A) mice presented normal CAP thresholds with broadened cochlear tuning. TRβ ~(E457A/E457A) and TRβ ~(Δ337T/Δ337T) presented developmental defects that led to a decreased width (P < 0.01) and an increased thickness (P<0.01) of the tectorial membrane. In addition, TRβ ~(Δ337T/Δ337T) animals showed an increased tectorial membrane area (P<0.01). Conclusion: Both mutations were deleterious to tectorial membrane development and led to important alterations in cochlear morphology and loss of cochlear function.
机译：甲状腺激素（THs）调节许多发育过程，包括耳蜗分化和功能的发育发作。 TH作用主要由与甲状腺激素核受体（TRs）结合的三碘甲状腺素（T3）介导。在正调控基因且无TH的情况下，核共阻遏物与TR结合并降低基础转录速率。配体（T _3）的结合导致辅阻遏物的解离和辅激活物向复合物的募集，从而导致完整的转录激活。方法：我们在两种敲入小鼠模型中测量了耳蜗功能：TRβ〜（E457A / E457A），TRβ辅助激活物结合表面（AF-2）被破坏以防止辅助激活物结合。 TRβ〜（Δ337T/Δ337T），不能结合T _3。在10周龄的正常和突变小鼠中分析了耳蜗的形态和功能。耳蜗功能是通过测量听觉脑干反应，耳蜗调节和复合动作电位（CAP）阈值来确定的。结果：所有TRβ〜（Δ337T/Δ337T）和85％的TRβ〜（E457A / E457A）小鼠的CAP阈值均升高（P <0.05或更低）。百分之五的TRβ〜（E457A / E457A）小鼠表现出正常的CAP阈值，并具有较大的耳蜗调节。 TRβ〜（E457A / E457A）和TRβ〜（Δ337T/Δ337T）出现发育缺陷，导致盖膜宽度减小（P <0.01）和厚度增加（P <0.01）。另外，TRβ〜（Δ337T/Δ337T）动物表现出增加的盖膜面积（P <0.01）。结论：这两个突变均对盖膜发育有害，并导致耳蜗形态的重大改变和耳蜗功能的丧失。

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