Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses
Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses
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DOI：
10.1016/j.mcn.2006.02.001
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发表时间：
2006-05-01
影响因子：
3.5
通讯作者：
Bassell, Gary J.
中科院分区：
文献类型：
--
作者：
Antar, Laura N.;Li, Chanxia;Bassell, Gary J.
mRNA结合蛋白FMRP的遗传缺陷导致了最常见的遗传形式的智力迟钝，脆性X综合征。我们研究了培养海马神经元发育过程中FMRP的定位和功能。FMRP分布在颗粒内，延伸到发育中的轴突和生长锥，在距离细胞体300 pro以上的距离可检测到。在成熟的培养中，FMRP颗粒存在于轴突和树突中，在轴突远端和突触附近间歇性地出现较高浓度的小袋。MAP1b mPNA，一个已知的FMRP靶点，也定位于轴突生长锥。FMR1 KO生长锥的形态计量学分析显示丝状足过多和运动性降低。在突触形成的后期，FMR1 KO神经元表现出过多的丝状足和沿树突的长棘，但突触前终末并列的棘状突起密度明显减少。相比之下，FMR1 KO和WT之间的轴突触密度没有差异。WT神经元的短暂去极化导致丝足和脊柱突触数量增加，而FMR1 KO神经元的树突没有观察到额外的形态学变化，而丝足-脊柱密度已经增加。这些发现表明，FMR1 KO神经元轴突生长和神经支配调节的改变可能有助于脆性X综合征的树突和脊柱病理。这项工作对理解mRNA结合蛋白在发育和蛋白质合成依赖的可塑性中的作用具有更广泛的意义。(c) 2006爱思唯尔公司版权所有。
Genetic deficiency of the mRNA binding protein FMRP results in the most common inherited form of mental retardation, Fragile X syndrome. We investigated the localization and function of FMRP during development of hippocampal neurons in culture. FMRP was distributed within granules that extended into developing axons and growth cones, detectable at distances over 300 pro from the cell body. In mature cultures, FMRP granules were present in both axons and dendrites, with pockets of higher concentrations appearing intermittently, along distal axon segments and near synapses. MAP1b mPNA, a known FMRP target, was also localized to axon growth cones. Morphometric analysis of growth cones from the FMR1 KO revealed both excess filopodia and reduced motility. At later stages during synapse formation, FMR1 KO neurons exhibited excessive filopodia and long spines along dendrites, yet there was a marked decrease in the density of spine-like protrusions juxtaposed to presynaptic terminals. In contrast, there was no difference in the density of shaft synapses between FMR1 KO and WT. Brief depolarization of WT neurons resulted in increased numbers of filopodia and spine synapses, whereas no additional morphologic changes were observable in dendrites of FMR1 KO neurons that already had increased density of filopodia-spines. These findings suggest that alterations in the regulation of axonal growth and innervation in FMR1 KO neurons may contribute to the dendritic and spine pathology in Fragile X syndrome. This work has broader implications for understanding the role of mRNA binding proteins in developmental and protein-synthesis-dependent plasticity. (c) 2006 Elsevier Inc. All rights reserved.