COUP-TF1 Modulates Thyroid Hormone Action in an Embryonic Stem-Cell Model of Cortical Pyramidal Neuronal Differentiation
COUP-TF1 Modulates Thyroid Hormone Action in an Embryonic Stem-Cell Model of Cortical Pyramidal Neuronal Differentiation
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COUP-TF1 在皮质锥体神经元分化的胚胎干细胞模型中调节甲状腺激素的作用
DOI：
10.1089/thy.2017.0256
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发表时间：
2018
期刊：
影响因子：
6.6
通讯作者：
Brent Gregory A.
中科院分区：
文献类型：
--
作者：
Teng Xiaochun;Liu Yan-Yun;Teng Weiping;Brent Gregory A.
背景：甲状腺激素对大脑的正常发育至关重要，并具有时空特异性。甲状腺激素过多或不足，可导致大脑和感觉发育不可逆转的损害。鸡卵清蛋白上游转录因子1（COUP-TF 1），在神经元发育的早期表达，是实现正常脑结构所必需的。方法：采用体外诱导小鼠胚胎干细胞（mES）分化为皮质神经元的方法，研究COUP-TF 1对脑发育过程中甲状腺激素信号通路的影响。mES细胞在特定的条件培养基中培养和分化，在第一阶段获得高百分比的nestin阳性前体神经元，在第二阶段获得具有特征性神经元firing.Results的皮质神经元：nestin阳性前体细胞的数量，如通过荧光激活细胞分选分析测定的，与对照相比，用三碘甲状腺原氨酸（T3）处理显著更大（p< 0.05）。T3增强皮质神经元标记物（Tbr 1和Rc 3）mRNA的表达。在COUP-TF 1敲低后，巢蛋白阳性祖细胞的数量与对照相比减少（p< 0.05），但数量随着T3处理而增加。COUP-TF 1基因敲低后测定皮质神经元基因标记物的mRNA。在T3的存在下，神经元标记物Emx 1，Tbr 1，Camkiv和Rc 3 mRNA的峰值表达在分化的第18天比对照细胞在第22天更早。结论：COUP-TF 1基因在调节T3刺激的Rc 3和Tbr 1基因表达的时间和强度方面起重要作用。
Background:Thyroid hormone is critical for normal brain development and acts in a spatial and temporal specific pattern. Thyroid hormone excess, or deficiency, can lead to irreversible impairment of brain and sensory development. Chicken ovalbumin upstream-transcription factor 1 (COUP-TF1), expressed early in neuronal development, is essential to achieve normal brain structure. Thyroid hormone stimulation of gene expression is inversely correlated with the level of COUP-TF1 expression.Methods:Anin vitromethod of differentiating mouse embryonic stem (mES) cells into cortical neurons was utilized to study the influence of COUP-TF1 on thyroid hormone signaling in brain development. mES cells were cultured and differentiated in specific conditioned media, and a high percentage of nestin-positive progenitor neurons in the first stage, and cortical neurons in the second stage, was obtained with characteristic neuronal firing.Results:The number of nestin-positive progenitors, as determined by fluorescence-activated cell sorting analysis, was significantly greater with triiodothyronine (T3) treatment compared to control (p< 0.05). T3 enhanced the expression of cortical neuron marker (Tbr1 and Rc3) mRNAs. After COUP-TF1 knockdown, the number of nestin-positive progenitors was reduced compared to control (p< 0.05), but the number increased with T3 treatment. The mRNA of cortical neuronal gene markers was measured after COUP-TF1 knockdown. In the presence of T3, the peak expression of neuron markers Emx1, Tbr1, Camkiv, and Rc3 mRNA was earlier, at day 18 of differentiation, compared to control cells, at day 22. Furthermore, after COUP-TF1 knockdown, T3 induction of Rc3 and Tbr1 mRNA was significantly enhanced compared to cells expressing COUP-TF1.Conclusion:These results indicate that COUP-TF1 plays an important role in modulating the timing and magnitude of T3-stimulated gene expression required for normal corticogenesis.