SUMOylation of FOXP1 regulates transcriptional repression via CtBP1 to drive dendritic morphogenesis.
SUMOylation of FOXP1 regulates transcriptional repression via CtBP1 to drive dendritic morphogenesis.
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DOI：
10.1038/s41598-017-00707-6
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发表时间：
2017-04-13
影响因子：
4.6
通讯作者：
Henley JM
中科院分区：
文献类型：
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作者：
Rocca DL;Wilkinson KA;Henley JM
Forkhead Box P (FOXP) 转录抑制因子在大脑发育中发挥着重要作用，其功能障碍会导致人类认知障碍。然而，人们对这些蛋白质的活性是如何调节的知之甚少。在这里，我们表明 FOXP1 在赖氨酸 670 处的 SUMO 化是招募共阻遏物 CtBP1 和转录抑制所必需的。 FOXP1 SUMOylation 受到神经元活动的严格控制，其中突触到细胞核的信号传导通过 NMDAR 和 L 型钙通道介导，导致 FOXP1 快速去 SUMOylation。培养的皮层神经元中 FOXP1 的敲低会阻碍树突的生长，并且这种表型不能通过用不可 SUMO 化的 FOXP1-K670R 突变体替换来挽救，这表明 FOXP1 的 SUMO 化对于调节适当的神经元形态发生至关重要。这些结果表明 FOXP1 的活动依赖性 SUMO 化可能是大脑早期皮质发育和神经元网络形成的重要介质。
Forkhead Box P (FOXP) transcriptional repressors play a major role in brain development and their dysfunction leads to human cognitive disorders. However, little is known about how the activity of these proteins is regulated. Here, we show that FOXP1 SUMOylation at lysine 670 is required for recruiting the co-repressor CtBP1 and transcriptional repression. FOXP1 SUMOylation is tightly controlled by neuronal activity, in which synapse to nucleus signalling, mediated via NMDAR and L-type calcium channels, results in rapid FOXP1 deSUMOylation. Knockdown of FOXP1 in cultured cortical neurons stunts dendritic outgrowth and this phenotype cannot be rescued by replacement with a non-SUMOylatable FOXP1-K670R mutant, indicating that SUMOylation of FOXP1 is essential for regulation of proper neuronal morphogenesis. These results suggest that activity-dependent SUMOylation of FOXP1 may be an important mediator of early cortical development and neuronal network formation in the brain.