Action of Thyroxine on the Survival and Neurite Maintenance of Cerebellar Granule Neurons in Culture
Action of Thyroxine on the Survival and Neurite Maintenance of Cerebellar Granule Neurons in Culture
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DOI：
10.1002/jnr.23519
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发表时间：
2015-04-01
影响因子：
4.2
通讯作者：
Tashiro, Tomoko
中科院分区：
文献类型：
--
作者：
Oyanagi, Koshi;Negishi, Takayuki;Tashiro, Tomoko
发育性甲状腺功能减退会导致小脑严重受损。为了解甲状腺激素（THs）在小脑发育中的作用，我们研究了三种不同的甲状腺激素，即甲状腺素（T4）、3,5,3 - 三碘甲腺原氨酸（T3）和3,3,5 - 三碘甲腺原氨酸（反T3；rT3）对培养的小脑颗粒神经元（CGNs）的存活和形态的影响，并发现了T4特有的新作用。出生后第6天获取的大鼠小脑颗粒神经元首先在含25 mM K⁺（K25）的含血清培养基中培养2天，然后切换到含生理浓度5 mM K⁺（K5）或K25的无血清培养基中，并再培养2或4天。小脑颗粒神经元在K5中发生凋亡，但在K25中存活。添加浓度为100 - 200 nM的T4（而非T3或rT3）能以剂量依赖的方式挽救小脑颗粒神经元在K5中的细胞死亡。此外，200 nM的T4在维持K5中小脑颗粒神经元的轴突方面也有效。在K5中，T4抑制了两个发育调控位点的tau蛋白磷酸化以及c - jun N - 末端激酶（JNK）的磷酸化，而JNK的磷酸化对于其激活和定位到轴突是必需的。这些结果表明，在小脑发育过程中，T4通过调节JNK的活性和定位，以一种不同于其他两种甲状腺激素的方式在细胞存活和轴突维持方面发挥其作用。（c）2014威利期刊公司
Developmental hypothyroidism causes severe impairments in the cerebellum. To understand the role of thyroid hormones (THs) in cerebellar development, we examined the effect of three different THs, thyroxine (T4), 3,5,3-triidothyronine (T3), and 3,3,5-triiodothyronine (reverse T3; rT3), on the survival and morphology of cerebellar granule neurons (CGNs) in culture and found novel actions specific to T4. Rat CGNs obtained at postnatal day 6 were first cultured for 2 days in serum-containing medium with 25 mM K+ (K25), then switched to serum-free medium with physiological 5 mM K+ (K5) or with K25 and cultured for an additional 2 or 4 days. CGNs underwent apoptosis in K5 but survived in K25. Addition of T4 at concentrations of 100-200 nM but not T3 or rT3 rescued CGNs from cell death in K5 in a dose-dependent manner. Furthermore, 200 nM T4 was also effective in maintaining the neurites of CGNs in K5. In K5, T4 suppressed tau phosphorylation at two developmentally regulated sites as well as phosphorylation of c-jun N-terminal kinase (JNK) necessary for its activation and localization to axons. These results suggest that, during cerebellar development, T4 exerts its activity in cell survival and neurite maintenance in a manner distinct from the other two thyroid hormones through regulating the activity and localization of JNK. (c) 2014 Wiley Periodicals, Inc.