Department of Occupational Health, Third Military Medical University, No.30 Gaotanyan Street, Chongqing 400038, China.
Department of Occupational Health, Third Military Medical University, No.30 Gaotanyan Street, Chongqing 400038, China.
Biochim Biophys Acta Mol Cell Res. 2017 Oct;1864(10):1900-1912. doi: 10.1016/j.bbamcr.2017.07.019. Epub 2017 Aug 2.
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.
甲状腺激素在中脑多巴胺能（DA）神经元发育中发挥着关键作用。然而，其潜在的分子机制在很大程度上尚不清楚。在这项研究中，我们揭示了甲状腺激素处理通过经典瞬时受体电位（TRPC）通道在腹侧中脑神经干细胞中引发显著的钙内流，并且这种钙信号对于甲状腺激素依赖性 DA 神经元分化是必需的。我们还发现，TRPC1 是在腹侧中脑神经干细胞中表达的主要 TRPC 通道，其对甲状腺激素有反应。此外，甲状腺激素通过其受体 alpha 1 在 DA 神经元分化过程中增加 TRPC1 的表达，并且重要的是，通过激活 TRPC1 通道产生钙信号。体内和体外基因沉默实验表明，TRPC1 介导的钙信号对于甲状腺激素依赖性 DA 神经元分化是必需的。最后，我们证实 OTX2 的激活依赖于 TRPC1 介导的钙信号，而 OTX2 是 DA 神经元发育的决定因素，其表达受甲状腺激素诱导。这些数据揭示了甲状腺激素如何调节从中脑神经干细胞发育而来的 DA 神经元的分子机制，特别赋予了 TRPC1 通道新的生理相关性。
