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Title: CDKL5, a Protein Associated with Rett Syndrome, Regulates Neuronal Morphogenesis via Rac1 Signaling
Author: Chen, Qian ; Zhu, Yong-Chuan ; Yu, Jing ; Miao, Sheng ; Zheng, Jing ; Xu, Li ; Zhou, Yang ; Li, Dan ; Zhang, Chi ; Tao, Jiong ; null(熊志奇)
Source: JOURNAL OF NEUROSCIENCE
Issued Date: 2010
Volume: 30, Issue:38, Pages:12777-12786
Keyword: SEVERE MENTAL-RETARDATION ; EARLY-ONSET SEIZURES ; INFANTILE SPASMS ; RHO-GTPASES ; MECP2 GENE ; HISTONE DEACETYLASE ; ACTIN CYTOSKELETON ; MUTATIONS ; GROWTH ; EXPRESSION
Subject: Neurosciences & Neurology
Corresponding Author: Xiong, ZQ (reprint author), Chinese Acad Sci, Inst Neurosci, Shanghai 200031, Peoples R China,xiongzhiqi@ion.ac.cn
English Abstract: 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.
Indexed Type: sci
Language: 英语
Content Type: 期刊论文
URI: http://ir.sibs.ac.cn/handle/331001/1574
Appears in Collections:神经所(总)_期刊论文
疾病神经生物学研究组_期刊论文

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Chen, Qian; Zhu, Yong-Chuan; Yu, Jing; Miao, Sheng; Zheng, Jing; Xu, Li; Zhou, Yang; Li, Dan; Zhang, Chi; Tao, Jiong; Xiong, Zhi-Qi.CDKL5, a Protein Associated with Rett Syndrome, Regulates Neuronal Morphogenesis via Rac1 Signaling,JOURNAL OF NEUROSCIENCE,2010,30(38):12777-12786
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