Critical Role of Types 2 and 3 Deiodinases in the Negative Regulation of Gene Expression by T3 in the Mouse Cerebral Cortex
Critical Role of Types 2 and 3 Deiodinases in the Negative Regulation of Gene Expression by T3 in the Mouse Cerebral Cortex
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DOI：
10.1210/en.2011-1905
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发表时间：
2012-06-01
期刊：
影响因子：
4.8
通讯作者：
Bernal, Juan
中科院分区：
文献类型：
--
作者：
Hernandez, Arturo;Morte, Beatriz;Bernal, Juan
甲状腺激素通过 T-3 与核受体结合介导的基因表达控制来调节大脑发育和功能。脑内 T-3 浓度受到调节 T-4 和 T-3 运输和代谢的稳态机制的严格控制。我们研究了失活酶 3 型脱碘酶 (D3) 在调节 30 岁小鼠大脑皮层中 43 个甲状腺激素依赖性基因中的作用。 D3 失活略微增加了 22 个正调控基因中的 2 个基因的表达，并显着降低了 21 个负调控基因中的 7 个基因的表达。给予高剂量的T-3导致野生型小鼠中12个阳性基因和3个阴性基因的表达发生显着变化。 D3 缺陷小鼠对 T-3 治疗的反应在基因数量和反应幅度上均得到增强，这证明了 D3 在调节 T-3 作用中的作用。将 D3 缺乏症与甲状腺功能减退症、甲状腺功能亢进症和 2 型脱碘酶 (D2) 缺乏症中观察到的基因表达影响进行比较，发现阴性基因比阳性基因对 D2 和 D3 缺乏症更敏感。这一观察结果表明，在正常生理条件下，D2 和 D3 在将局部 T-3 浓度维持在非常窄的范围内方面发挥着关键作用。它还表明负向和正向调节的基因不具有相同的生理意义，或者甲状腺激素对它们的调节在分子或细胞水平上遵循不同的范式。 （内分泌学153：2919-2928，2012）
Thyroid hormones regulate brain development and function through the control of gene expression, mediated by binding of T-3 to nuclear receptors. Brain T-3 concentration is tightly controlled by homeostatic mechanisms regulating transport and metabolism of T-4 and T-3. We have examined the role of the inactivating enzyme type 3 deiodinase (D3) in the regulation of 43 thyroid hormone-dependent genes in the cerebral cortex of 30-d-old mice. D3 inactivation increased slightly the expression of two of 22 positively regulated genes and significantly decreased the expression of seven of 21 negatively regulated genes. Administration of high doses of T-3 led to significant changes in the expression of 12 positive genes and three negative genes in wild-type mice. The response to T-3 treatment was enhanced in D3-deficient mice, both in the number of genes and in the amplitude of the response, demonstrating the role of D3 in modulating T-3 action. Comparison of the effects on gene expression observed in D3 deficiency with those in hypothyroidism, hyperthyroidism, and type 2 deiodinase (D2) deficiency revealed that the negative genes are more sensitive to D2 and D3 deficiencies than the positive genes. This observation indicates that, in normal physiological conditions, D2 and D3 play critical roles in maintaining local T-3 concentrations within a very narrow range. It also suggests that negatively and positively regulated genes do not have the same physiological significance or that their regulation by thyroid hormone obeys different paradigms at the molecular or cellular levels. (Endocrinology 153: 2919-2928, 2012)