Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140
Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140
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DOI：
10.1016/j.neuron.2018.10.008
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发表时间：
2018-12-05
期刊：
影响因子：
16.2
通讯作者：
Kawabe, Hiroshi
中科院分区：
文献类型：
--
作者：
Ambrozkiewicz, Mateusz C.;Schwark, Manuela;Kawabe, Hiroshi
轴突-树突极性的建立是哺乳动物皮层发育过程中神经元径向迁移的基础。我们证明 E3 泛素连接酶 WW 含蛋白 1 和 2（Wwp1 和 Wwp2）对于发育中的神经元的正确极化是必不可少的。我们发现，敲除 Wwp1 和 Wwp2 会导致锥体神经元轴突树突极性缺陷及其异常的层状皮质分布。 Wwp2 内含子中编码的 miR-140 的敲除会产生与 Wwp1 和 Wwp2 删除类似的表型变化。有趣的是，神经元中 Wwp1 和 Wwp2/miR-140 位点的转录是由转录因子 Sox9 诱导的。最后，我们提供证据表明 miR-140 通过抑制 Fyn 激酶 mRNA 来监督轴突树突极性的建立。我们的数据描绘了一种新的调控途径，涉及轴突规范、锥体形态的获取和皮质神经元的适当层状分布所需的 Sox9-[Wwp1/Wwp2/miR-140]-Fyn。
The establishment of axon-dendrite polarity is fundamental for radial migration of neurons during cortex development of mammals. We demonstrate that the E3 ubiquitin ligases WW-Containing Proteins 1 and 2 (Wwp1 and Wwp2) are indispensable for proper polarization of developing neurons. We show that knockout of Wwp1 and Wwp2 results in defects in axon-dendrite polarity in pyramidal neurons, and their aberrant laminar cortical distribution. Knockout of miR-140, encoded in Wwp2 intron, engenders phenotypic changes analogous to those upon Wwp1 and Wwp2 deletion. Intriguingly, transcription of the Wwp1 and Wwp2/miR-140 loci in neurons is induced by the transcription factor Sox9. Finally, we provide evidence that miR-140 supervises the establishment of axon-dendrite polarity through repression of Fyn kinase mRNA. Our data delineate a novel regulatory pathway that involves Sox9-[Wwp1/Wwp2/miR-140]-Fyn required for axon specification, acquisition of pyramidal morphology, and proper laminar distribution of cortical neurons.