Rac is required for the survival of cortical neurons
Rac is required for the survival of cortical neurons
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DOI：
10.1016/j.expneurol.2022.114316
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发表时间：
2023-01-05
影响因子：
5.3
通讯作者：
Inoue, Norimitsu
中科院分区：
文献类型：
--
作者：
Katayama, Kei-ichi;Zheng, Yi;Inoue, Norimitsu
Rac1 是小 Rho GTPases 的成员，参与神经元细胞的多种细胞过程。 Rac1 在发育过程中发挥着特别重要的作用，并且已经使用 Rac1 缺陷小鼠对其作用进行了广泛研究。 Rac3 是 Rac1 的密切同源物，在神经系统中普遍表达，因此可能在 Rac1 缺陷细胞中补偿 Rac1。因此，探索 Rac 在神经元中的作用可能很困难。因此，我们删除了皮质神经元中的 Rac1 和 Rac3。 Rac缺陷的大脑皮层在出生时形成轻微发育不全但几乎正常的分层结构，但皮层神经元在出生后不久就会发生凋亡。 Rac缺陷的皮质神经元存活能力差，体外神经突长度和数量减少。 Rac 缺陷的皮质神经元中 Rac 下游效应器 Pak1 的激活可挽救其体外存活能力。 Pak1 激活的 Rac 缺陷神经元有大量树突，但没有轴突。 p35（Cdk5 的调节因子）的恢复在体外和体内部分挽救了 Rac 缺陷神经元的生存能力。 p35 的表达还部分地挽救了体外 Rac 缺陷神经元中神经突的长度和数量。 Rac被证明对于皮质神经元的存活是不可或缺的，Pak1和Cdk5/p35作为Rac的下游效应器促进神经元的存活。
Rac1, a member of small Rho GTPases, is involved in diverse cellular processes in neuronal cells. Rac1 plays especially important roles during development, and its roles have been extensively studied using Rac1-deficient mice. Rac3, a close homolog of Rac1, is ubiquitously expressed in the nervous system and may therefore compensate for Rac1 in Rac1-deficient cells. Exploration of the roles of Rac in neurons may therefore be difficult. We thus deleted both Rac1 and Rac3 in cortical neurons. Rac-deficient cerebral cortices formed slightly hypo-plastic but almost normally layered structures at birth, but cortical neurons underwent apoptosis soon after birth. Rac-deficient cortical neurons had poor survivability and there was reduction in the length and the number of neurites in vitro. Activation of Pak1, a downstream effector of Rac, in Rac-deficient cortical neurons rescued the survivability in vitro. Pak1-activated Rac-deficient neurons had numerous dendrites, but no axons. Restoration of p35, a regulator of Cdk5, partly rescued the survivability of Rac-deficient neurons both in vitro and in vivo. Expression of p35 also partly rescued the length and the number of neurites in Rac-deficient neurons in vitro. Rac was shown to be indispensable for the survival of cortical neurons, and Pak1 and Cdk5/p35 work as downstream effectors of Rac to promote neuronal survival.