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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling.
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CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling.

机译：CDK15，一种与Rett综合征相关的蛋白质，通过RAC1信号传导调节神经元形态发生。

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Mutations in cyclin-dependent kinase-like 5 (CDKL5), also known as serine/threonine kinase 9 (STK9), have been identified in patients with Rett syndrome (RTT) and X-linked infantile spasm. However, the function of CDKL5 in the brain remains unknown. Here, we report that CDKL5 is a critical regulator of neuronal morphogenesis. We identified a neuron-specific splicing variant of CDKL5 whose expression was markedly induced during postnatal development of the rat brain. Downregulating CDKL5 by RNA interference (RNAi) in cultured cortical neurons inhibited neurite growth and dendritic arborization, whereas overexpressing CDKL5 had opposite effects. Furthermore, knocking down CDKL5 in the rat brain by in utero electroporation resulted in delayed neuronal migration, and severely impaired dendritic arborization. In contrast to its proposed function in the nucleus, we found that CDKL5 regulated dendrite development through a cytoplasmic mechanism. In fibroblasts and in neurons, CDKL5 colocalized and formed a protein complex with Rac1, a critical regulator of actin remodeling and neuronal morphogenesis. Overexpression of Rac1 prevented the inhibition of dendrite growth caused by CDKL5 knockdown, and the growth-promoting effect of ectopically expressed CDKL5 on dendrites was abolished by coexpressing a dominant-negative form of Rac1. Moreover, CDKL5 was required for brain-derived neurotrophic factor (BDNF)-induced activation of Rac1. Together, these results demonstrate a critical role of CDKL5 in neuronal morphogenesis and identify a Rho GTPase signaling pathway which may contribute to CDKL5-related disorders.
机译：在细胞周期蛋白依赖性激酶样5（CDKL5），也被称为丝氨酸/苏氨酸激酶9突变（STK9），已在患者Rett综合征（RTT）和X-连锁婴儿痉挛被确定。然而，CDKL5在脑功能仍是未知。在这里，我们报告说，CDKL5是神经元形态发生的一个关键调节器。我们确定CDKL5的神经元特异性剪接变异的表达大鼠脑的发育阶段的显着诱导。下调CDKL5通过在培养的皮层神经元的RNA干扰（RNAi）抑制神经突生长和树突分支，而过表达CDKL5有相反的作用。此外，在子宫内电撞倒CDKL5大鼠脑内通过导致迟发性神经细胞迁移和严重受损树突分支。与在细胞核中其提出的功能，我们发现，通过CDKL5细胞质机制调节树突发育。在成纤维细胞和神经元中，共定位CDKL5和形成的复合物与Rac1蛋白，肌动蛋白重塑和神经元形态的关键调节的蛋白质。 Rac1的过表达防止因CDKL5击倒枝晶生长的抑制，和异位表达CDKL5对树突生长促进作用由共表达的Rac1的显性负形式废除。此外，CDKL5被需要脑源性神经营养因子（BDNF）的Rac1的活化诱导的。总之，这些结果表明CDKL5在神经元形态发生中起关键作用，并确定作为Rho GTPase信号通路可能有助于CDKL5相关疾病。

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