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
	Xiong, Zhi-Qi
刊名	JOURNAL OF NEUROSCIENCE
	2010
卷号	30 期号:38 页码:12777-12786
关键词	SEVERE MENTAL-RETARDATION EARLY-ONSET SEIZURES INFANTILE SPASMS RHO-GTPASES MECP2 GENE HISTONE DEACETYLASE ACTIN CYTOSKELETON MUTATIONS GROWTH EXPRESSION
ISSN号	0270-6474
通讯作者	Xiong, ZQ (reprint author), Chinese Acad Sci, Inst Neurosci, Shanghai 200031, Peoples R China,xiongzhiqi@ion.ac.cn
英文摘要	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.
学科主题	Neurosciences & Neurology
收录类别	SCI
资助信息	National Basic Research Program of China[2006CB806600]; Key State Research Program of China[2006CB943900]; National Natural Science Foundation of China[30721004, 30925016, 30500292]; Shanghai Municipal Education Commission; Shanghai Education Development Foundation[06SG21]
语种	英语
公开日期	2012-07-13
内容类型	期刊论文
源URL	[http://ir.sibs.ac.cn/handle/331001/1574]
专题	上海神经科学研究所_神经所(总) 上海神经科学研究所_疾病神经生物学研究组
推荐引用方式 GB/T 7714	Xiong, Zhi-Qi. CDKL5, a Protein Associated with Rett Syndrome, Regulates Neuronal Morphogenesis via Rac1 Signaling[J]. JOURNAL OF NEUROSCIENCE,2010,30(38):12777-12786.
APA	Xiong, Zhi-Qi.(2010).CDKL5, a Protein Associated with Rett Syndrome, Regulates Neuronal Morphogenesis via Rac1 Signaling.JOURNAL OF NEUROSCIENCE,30(38),12777-12786.
MLA	Xiong, Zhi-Qi."CDKL5, a Protein Associated with Rett Syndrome, Regulates Neuronal Morphogenesis via Rac1 Signaling".JOURNAL OF NEUROSCIENCE 30.38(2010):12777-12786.