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- Title
CDKL5, a Protein Associated with Rett Syndrome, Regulates Neuronal Morphogenesis via Rac1 Signaling.
- Authors
Qian Chen; Yong-Chuan Zh; Jing Yu; Sheng Miao; Jing Zheng; Li Xu; Yang Zhou; Dan Li; Chi Zhang; Jiong Tao; Zhi-Qi Xiong
- 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 (Rh) 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 Raci, a critical regulator of actin remodeling and neuronal morphogenesis. Overexpression ofRaci 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 Raci. Moreover, CDKL5 was required for brain-derived neurotrophic factor (BDNF)-induced activation of Raci. 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.
- Subjects
RETT syndrome; GENETIC mutation; MORPHOGENESIS; INFANTILE spasms; ELECTROPORATION; DENDRITIC cells; FIBROBLASTS; RHO GTPases
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 38, p12777
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1102-10.2010