Wdr47 Controls Neuronal Polarization through the Camsap Family Microtubule Minus-End-Binding Proteins
Wdr47 Controls Neuronal Polarization through the Camsap Family Microtubule Minus-End-Binding Proteins
复制标题
Wdr47 通过 Camsap 家族微管负端结合蛋白控制神经元极化
DOI：
10.1016/j.celrep.2020.107526
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发表时间：
2020-04-21
期刊：
影响因子：
8.8
通讯作者：
Zhu, Xueliang
中科院分区：
文献类型：
--
作者：
Chen, Yawen;Zheng, Jianqun;Zhu, Xueliang
神经元需要适当的极化来精确定位和轴突-树突的形成。人们对它们的内在调节机制和潜在机制知之甚少。这里，我们展示了Wdr47是一个关键的偏振调节因子。Wdr47基因缺陷的新生小鼠死于窒息，原因是中枢神经系统缺陷，包括轴索发育不全和放射状迁移减慢。Wdr47缺陷抑制了皮质神经元的多极-双极转变，降低了轴突顶端导向的微管动力学，并导致多轴突的形成。Wdr47在野生型神经元中的过表达抑制了轴突的指定，并中和了紫杉醇诱导的轴突过度生长和轴突过度生产。Wdr47与微管负端结合蛋白Camsap家族相互作用；通过Camsap 3与微管结合，其基因破坏也会导致多个轴突；并促进Camap 3在未极化神经元的神经突起中积累。此外，Camsap的过表达挽救了Wdr47缺失神经元的极化缺陷。我们的结果表明，在神经元极化的早期阶段，Wdr47通过Camsaps促进适当的轴突重塑，以微调局部微管的动力学和组织。
Neurons require proper polarization for precise positioning and axon-dendrite formation. Their intrinsic regulators and underlying mechanisms are poorly understood. Here, we show that Wdr47 is a key polarization regulator. Wdr47-deficient newborn mice die of suffocation due to central nervous system defects including axonal tracts agenesis and slowed radial migration. Wdr47 deficiency represses the multipolar-bipolar transition of cortical neurons, reduces neurite tip-directed microtubule dynamics, and causes multi-axon formation. Overexpression of Wdr47 in wild-type neurons inhibits axon specification and neutralizes Taxol-induced neurite over-growth and axon overproduction. Wdr47 interacts with the Camsap family of microtubule minus-endbinding proteins; associates with microtubules through Camsap3, whose gene disruption also causes multi-axons; and promotes Camsap3 accumulation in neurites of unpolarized neurons. Furthermore, Camsap overexpression rescues the polarization defects of Wdr47-deficient neurons. Our results indicate that Wdr47 facilitates proper neurite remodeling through Camsaps to fine-tune regional microtubule dynamics and organization during early stages of neuronal polarization.