STK25 and MST3 Have Overlapping Roles to Regulate Rho GTPases during Cortical Development
STK25 and MST3 Have Overlapping Roles to Regulate Rho GTPases during Cortical Development
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DOI：
10.1523/jneurosci.0523-21.2021
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发表时间：
2021-10-27
影响因子：
5.3
通讯作者：
Nakayama, Atsuo
中科院分区：
文献类型：
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作者：
Matsuki, Tohru;Iio, Akio;Nakayama, Atsuo
神经元迁移的精确控制是新皮层的层状组织所必需的，对脑功能至关重要。我们以前报道，急性中断的Stk 25基因（Stk 25条件性敲除; cKO）在小鼠胚胎发育过程中导致异常的神经元迁移的新皮层，但矛盾的是，Stk 25 cKO没有皮质表型，这表明存在某种形式的补偿。在这项研究中，我们报告，MST 3，另一个成员的GCKIII亚组的Ste 20样激酶家族，补偿损失的Stk 25，反之亦然，与性别无关的方式。MST 3过表达挽救了Stk 25 cKO脑中的神经元迁移缺陷和异常轴突发生。从机制上讲，STK 25导致发育中大脑中Rac 1激活和RhoA水平降低，这两者都是完全恢复Stk 25 cKO大脑中神经元迁移所必需的。异常迁移表型也被Bacurd 1和Cul 3的过表达所拯救，Bacurd 1和Cul 3靶向RhoA降解，并激活Rac 1。这项研究表明，MST 3上调能够挽救急性Stk 25缺乏症，并解决了皮质生成所需的下游STK 25信号传导的细节，这与MST 3信号传导是共同的，也是不同的。
Precise control of neuronal migration is required for the laminar organization of the neocortex and critical for brain function. We previously reported that the acute disruption of the Stk25 gene (Stk25 conditional knock-out; cKO) during mouse embryogenesis causes anomalous neuronal migration in the neocortex, but paradoxically the Stk25 cKO did not have a cortical phenotype, suggesting some forms of compensation exist. In this study, we report that MST3, another member of the GCKIII subgroup of the Ste20-like kinase family, compensates for loss of Stk25 and vice versa with sex independent manner. MST3 overexpression rescued neuronal migration deficit and abnormal axonogenesis in Stk25 cKO brains. Mechanistically, STK25 leads to Rac1 activation and reduced RhoA levels in the developing brain, both of which are required to fully restore neuronal migration in the Stk25 cKO brain. Abnormal migration phenotypes are also rescued by overexpression of Bacurd1and Cul3, which target RhoA for degradation, and activate Rac1. This study reveals that MST3 upregulation is capable of rescuing acute Stk25 deficiency and resolves details of signaling downstream STK25 required for corticogenesis both common to and distinct from MST3 signaling.