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The Journal of Neuroscience, October 7, 2009, 29(40):12419-12427; doi:10.1523/JNEUROSCI.5954-08.2009

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Development/Plasticity/Repair
Modulation of Neuritogenesis by a Protein Implicated in X-Linked Mental Retardation

Xinfu Jiao, Hongxin Chen, Jianmin Chen, Karl Herrup, Bonnie L. Firestein, and Megerditch Kiledjian

Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082

Correspondence should be addressed to Megerditch Kiledjian, Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ 08854-8082. Email: kiledjian{at}biology.rutgers

Posttranscriptional regulation is an important control mechanism governing gene expression in neurons. We recently demonstrated that VCX-A, a protein implicated in X-linked mental retardation, is an RNA-binding protein that specifically binds the 5' end of capped mRNAs to prevent their decapping and decay. Previously, expression of VCX-A was reported to be testes restricted. Consistent with a role in cognitive function, we demonstrate that VCX-A is ubiquitously expressed in human tissues including the brain. Moreover, retinoic acid-induced differentiation of human SH-SY5Y neuroblastoma cells promoted the accumulation of VCX-A in distinct cytoplasmic foci within neurites that colocalize with staufen1-containing RNA granules, suggesting a role in translational suppression and/or mRNA transport. Exogenous expression of VCX-A in rat primary hippocampal neurons, which normally do not express the primate-restricted VCX proteins, promoted neurite arborization, and shRNA-directed knockdown of the VCX genes in SH-SY5Y cells resulted in a reduction of both primary and secondary neurite projections upon differentiation. We propose that the cap-binding property of VCX-A reflects a role of this protein in mRNA translational regulation. In support of this hypothesized role, we demonstrate that VCX-A can specifically bind a subset of mRNAs involved in neuritogenesis and is also capable of promoting translational silencing. Thus, VCX-A contains the capacity to modulate the stability and translation of a subset of target mRNAs involved in neuronal differentiation and arborization. It is plausible that defects of these functions in the absence of the VCX genes could contribute to a mental retardation phenotype.

Received Dec. 15, 2008; revised Aug. 7, 2009; accepted Aug. 27, 2009.

Correspondence should be addressed to Megerditch Kiledjian, Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ 08854-8082. Email: kiledjian{at}biology.rutgers


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