A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome
A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome
复制标题
DOI：
10.1016/j.devcel.2008.04.003
复制
发表时间：
2008-06-01
影响因子：
11.8
通讯作者：
Bassell, Gary J.
中科院分区：
文献类型：
--
作者：
Dictenberg, Jason B.;Swanger, Sharon A.;Bassell, Gary J.
在脆性X综合征（FXS）中，局部蛋白质合成在突触可塑性及其失调中的作用已得到充分研究，但受调节的mRNA转运对此功能的贡献仍不清楚。我们报告了脆性X智力低下蛋白（FMRP）在突触发生和可塑性重要的mRNA的快速，活性调节运输中的功能。mRNA缺乏在神经元中的神经元的Fmr1基因敲除小鼠，和单个mRNA粒子动力学活神经元中的多巴胺能信号诱导的树突定位显示减少运动。FMRP和同源mRNA的运动依赖性易位涉及FMRP和驱动蛋白轻链的C末端，KO脑显示驱动蛋白相关mRNA减少。WT神经元中FMRP和靶mRNA转运的急性抑制导致模拟FXS表型的丝状伪足-棘形态改变。这些发现突出了刺激诱导的树突状mRNA运输的机制，并将其在FXS小鼠模型中的损伤与发育形态可塑性的改变联系起来。
The function of local protein synthesis in synaptic plasticity and its dysregulation in fragile X syndrome (FXS) is well studied, however the contribution of regulated mRNA transport to this function remains unclear. We report a function for the fragile X mental retardation protein (FMRP) in the rapid, activity-regulated transport of mRNAs important for synaptogenesis and plasticity. mRNAs were deficient in glutamatergic signaling-induced dendritic localization in neurons from Fmr1 KO mice, and single mRNA particle dynamics in live neurons revealed diminished kinesis. Motor-dependent translocation of FMRP and cognate mRNAs involved the C terminus of FMRP and kinesin light chain, and KO brain showed reduced kinesin-associated mRNAs. Acute suppression of FMRP and target mRNA transport in WT neurons resulted in altered filopodia-spine morphology that mimicked the FXS phenotype. These findings highlight a mechanism for stimulus-induced dendritic mRNA transport and link its impairment in a mouse model of FXS to altered developmental morphologic plasticity.