Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan.
Dev Neurobiol. 2019 Jan;79(1):60-74. doi: 10.1002/dneu.22653. Epub 2018 Nov 28.
Regulated local translation-whereby specific mRNAs are transported and localized in subcellular domains where they are translated in response to regional signals-allows for remote control of gene expression to concentrate proteins in subcellular compartments. Neurons are highly polarized cells with unique features favoring local control for axonal pathfinding and synaptic plasticity, which are key processes involved in constructing functional circuits in the developing brain. Neurodevelopmental disorders are caused by genetic or environmental factors that disturb the nervous system's development during prenatal and early childhood periods. The growing list of genetic mutations that affect mRNA translation raises the question of whether aberrant translatomes in individuals with neurodevelopmental disorders share common molecular features underlying their stereotypical phenotypes and, vice versa, cause a certain degree of phenotypic heterogeneity. Here, we briefly give an overview of the role of local translation during neuronal development. We take the autism-risk gene list and discuss the molecules that (perhaps) are involved in mRNA transport and translation. Both exaggerated and suppressed translation caused by mutations in those genes have been identified or suggested. Finally, we discuss some proof-of-principle regimens for use in autism mouse models to correct dysregulated translation.
受调控的局部翻译——特定的 mRNA 被运输并定位于亚细胞区域，在这些区域中，它们会响应区域信号进行翻译——使得远程控制基因表达成为可能，将蛋白质集中在亚细胞隔室中。神经元是高度极化的细胞，具有独特的特征，有利于轴突寻路和突触可塑性的局部控制，而这两者是构建发育中大脑功能回路的关键过程。神经发育障碍是由遗传或环境因素引起的，这些因素会在产前和儿童早期干扰神经系统的发育。越来越多的影响 mRNA 翻译的基因突变提出了一个问题，即神经发育障碍患者的异常翻译组是否具有其典型表型的共同分子特征，如果是这样，它们是否会导致一定程度的表型异质性。在这里，我们简要概述了局部翻译在神经元发育中的作用。我们以自闭症风险基因列表为基础，讨论了那些（可能）参与 mRNA 运输和翻译的分子。已经确定或提出了这些基因中的突变导致的翻译过度和翻译抑制。最后，我们讨论了一些在自闭症小鼠模型中用于纠正失调翻译的原理验证方案。
