Critical role of TRPC1 in thyroid hormone-dependent dopaminergic neuron development
Critical role of TRPC1 in thyroid hormone-dependent dopaminergic neuron development
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TRPC1 在甲状腺激素依赖性多巴胺能神经元发育中的关键作用
DOI：
10.1016/j.bbamcr.2017.07.019
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发表时间：
2017-10-01
影响因子：
5.1
通讯作者：
Zhou, Zhou
中科院分区：
文献类型：
--
作者：
Chen, Chunhai;Ma, Qinglong;Zhou, Zhou
甲状腺激素在中脑多巴胺能神经元发育中起着至关重要的作用。然而，其潜在的分子机制在很大程度上仍不清楚。在本研究中，我们揭示了甲状腺激素治疗通过规范的瞬时受体电位(TRPC)通道在腹侧中脑神经干细胞上引起了显著的钙内流，这种钙信号对甲状腺激素依赖的DA神经元的分化是必不可少的。我们还发现，TRPC1是腹侧中脑神经干细胞表达的主要TRPC通道，对甲状腺激素有反应。此外，在DA神经元分化过程中，甲状腺激素通过其受体α1增加TRPC1的表达，更重要的是，通过激活TRPC1通道产生钙信号。体内和体外的基因沉默实验表明，TRPC1介导的钙信号是甲状腺激素依赖的DA神经元分化所必需的。最后，我们证实OTX2的激活依赖于TRPC1介导的钙信号。OTX2是DA神经元发育的决定因素，其表达是由甲状腺激素诱导的。这些数据揭示了甲状腺激素如何调节腹侧中脑神经干细胞DA神经元发育的分子机制，特别是赋予TRPC1通道一个新的生理相关性。
Thyroid hormones play a crucial role in midbrain dopaminergic (DA) neuron development. However, the underlying molecular mechanisms remain largely unknown. In this study, we revealed that thyroid hormone treatment evokes significant calcium entry through canonical transient receptor potential (TRPC) channels in ventral midbrain neural stem cells and this calcium signaling is essential for thyroid hormone-dependent DA neuronal differentiation. We also found that TRPC1 is the dominant TRPC channel expressed in ventral midbrain neural stem cells which responds to thyroid hormone. In addition, thyroid hormone increases TRPC1 expression through its receptor alpha 1 during DA neuron differentiation, and, importantly, produces calcium signals by activating TRPC1 channels. In vivo and in vitro gene silencing experiments indicate that TRPC1-mediated calcium signaling is required for thyroid hormone-dependent DA neuronal differentiation. Finally, we confirmed that the activation of OTX2, a determinant of DA neuron development and the expression of which is induced by thyroid hormone, is dependent on TRPC1-mediated calcium signaling. These data revealed the molecular mechanisms of how thyroid hormone regulates DA neuron development from ventral midbrain neural stem cells, particularly endowing a novel physiological relevance to TRPC1 channels.