Modulation of Neuritogenesis by a Protein Implicated in X-Linked Mental Retardation
Modulation of Neuritogenesis by a Protein Implicated in X-Linked Mental Retardation
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DOI：
10.1523/jneurosci.5954-08.2009
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发表时间：
2009-10-07
影响因子：
5.3
通讯作者：
Kiledjian, Megerditch
中科院分区：
文献类型：
--
作者：
Jiao, Xinfu;Chen, Hongxin;Kiledjian, Megerditch
转录后调控是神经元基因表达的重要控制机制。我们最近证明，VCX-A（一种与 X 连锁智力低下有关的蛋白质）是一种 RNA 结合蛋白，可特异性结合加帽 mRNA 的 5' 端，以防止其脱帽和腐烂。此前，据报道 VCX-A 的表达受到睾丸的限制。与认知功能中的作用一致，我们证明 VCX-A 在包括大脑在内的人体组织中普遍表达。此外，视黄酸诱导的人SH-SY5Y神经母细胞瘤细胞的分化促进了VCX-A在神经突内不同细胞质灶中的积累，这些灶与含有staufen1的RNA颗粒共定位，表明VCX-A在翻译抑制和/或mRNA运输中发挥作用。大鼠原代海马神经元通常不表达灵长类限制的 VCX 蛋白，VCX-A 在大鼠原代海马神经元中的外源表达促进神经突树枝化，SH-SY5Y 细胞中 shRNA 指导的 VCX 基因敲低导致分化时初级和次级神经突投射减少。我们认为 VCX-A 的帽结合特性反映了该蛋白在 mRNA 翻译调节中的作用。为了支持这一假设的作用，我们证明 VCX-A 可以特异性结合参与神经突发生的 mRNA 子集，并且还能够促进翻译沉默。因此，VCX-A 具有调节参与神经元分化和树枝化的靶 mRNA 子集的稳定性和翻译的能力。在缺乏 VCX 基因的情况下，这些功能的缺陷可能会导致智力迟钝表型。
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.