Critical role of TRPC1 in thyroid hormone-dependent dopaminergic neuron development

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.