The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival.
The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival.
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DOI：
10.1016/j.cell.2018.07.046
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发表时间：
2018-09-06
期刊：
影响因子：
64.5
通讯作者：
Shen K
中科院分区：
文献类型：
--
作者：
Maeder CI;Kim JI;Liang X;Kaganovsky K;Shen A;Li Q;Li Z;Wang S;Xu XZS;Li JB;Xiang YK;Ding JB;Shen K
突触囊泡和活性区蛋白是突触发生所必需的。这些蛋白质协同合成的分子机制尚不清楚。利用正向遗传筛选，我们鉴定了保守的THO核输出复合物（THOC）是C.秀丽多巴胺能神经元。在THOC突变体中，突触信使RNA保留在细胞核中，导致突触蛋白表达的急剧减少，突触几乎完全丧失，多巴胺功能受损。CRE结合蛋白（CREB）与THOC相互作用以标记突触转录物用于有效的核输出。小鼠多巴胺能神经元中THOC亚基Td5的缺失导致突触维持的严重缺陷和随后的黑质致密神经元死亡。这些细胞缺陷导致多巴胺释放的取消、共济失调和动物死亡。总之，我们的研究结果表明，核输出机制可以选择特定的mRNA，是神经元分化和存活的限速步骤。
Synaptic vesicle and active zone proteins are required for synaptogenesis. The molecular mechanisms for coordinated synthesis of these proteins are not understood. Using forward genetic screens, we identified the conserved THO nuclear export Complex (THOC) as an important regulator of presynapse development in C. elegans dopaminergic neurons. In THOC mutants, synaptic messenger RNAs are retained in the nucleus, resulting in dramatic decrease of synaptic protein expression, near complete loss of synapses and compromised dopamine function. CRE binding protein (CREB) interacts with THOC to mark synaptic transcripts for efficient nuclear export. Deletion of Thoc5, a THOC subunit, in mouse dopaminergic neurons causes severe defects in synapse maintenance and subsequent neuronal death in the Substantia Nigra Compacta. These cellular defects lead to abrogated dopamine release, ataxia and animal death. Together, our results argue that nuclear export mechanisms can select specific mRNAs and be a rate-limiting step for neuronal differentiation and survival.