Temporal requirements of the fragile X mental retardation protein in the regulation of synaptic structure
Temporal requirements of the fragile X mental retardation protein in the regulation of synaptic structure
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DOI：
10.1242/dev.022244
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发表时间：
2008-08-01
期刊：
影响因子：
4.6
通讯作者：
Broadie, Kendal
中科院分区：
文献类型：
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作者：
Gatto, Cheryl L.;Broadie, Kendal
脆性X综合征（FraX），由一个基因（FMR 1）的功能丧失引起，是智力迟钝和自闭症谱系障碍最常见的遗传形式。FMR 1产物（FMRP）是一种mRNA结合翻译调节因子，介导突触结构和功能的活性依赖性控制。为了开发任何FraX干预策略，必须确定FMRP丢失何时何地导致突触缺陷的表现，以及重新引入FMRP是否可以恢复正常的突触特性。在果蝇FraX模型中，dFMRP缺失导致神经肌肉接头（NMJ）突触过度发育（过度生长、过度分支、过量突触终扣）、发育停滞卫星终扣的积累和神经传递改变。我们使用基因开关方法有条件地驱动dFMRP表达，以定义突触机制中的时空要求。在野生型水平上组成型诱导靶向神经元dFMRP拯救了果蝇Fmr 1（dfmr 1）无效突变体中所有突触结构缺陷，表明突触结构的突触前要求。相比之下，突触前dFMRP表达并不改善功能性神经传递缺陷，表明突触后dFMRP的要求。引人注目的是，有针对性的早期诱导dFMRP效应几乎完全拯救突触结构缺陷，显示出主要的早期发育作用。此外，急性dFMRP表达在成熟时，部分deletates dfmr 1-null缺陷，虽然救援是不完整的早期或组成型dFMRP表达，显示出适度的能力，后期结构可塑性。我们的结论是，dFMRP主要作用于早期突触发生，以调节架构，但晚dFMRP引进成熟时可以弱补偿早期缺乏dFMRP功能。
Fragile X syndrome (FraX), caused by the loss-of-function of one gene ( FMR1), is the most common inherited form of both mental retardation and autism spectrum disorders. The FMR1 product ( FMRP) is an mRNA-binding translation regulator that mediates activity-dependent control of synaptic structure and function. To develop any FraX intervention strategy, it is essential to define when and where FMRP loss causes the manifestation of synaptic defects, and whether the reintroduction of FMRP can restore normal synapse properties. In the Drosophila FraX model, dFMRP loss causes neuromuscular junction (NMJ) synapse over-elaboration ( overgrowth, overbranching, excess synaptic boutons), accumulation of development-arrested satellite boutons, and altered neurotransmission. We used the Gene-Switch method to conditionally drive dFMRP expression to define the spatiotemporal requirements in synaptic mechanisms. Constitutive induction of targeted neuronal dFMRP at wild-type levels rescues all synaptic architectural defects in Drosophila Fmr1 (dfmr1)-null mutants, demonstrating a presynaptic requirement for synapse structuring. By contrast, presynaptic dFMRP expression does not ameliorate functional neurotransmission defects, indicating a postsynaptic dFMRP requirement. Strikingly, targeted early induction of dFMRP effects nearly complete rescue of synaptic structure defects, showing a primarily early-development role. In addition, acute dFMRP expression at maturity partially alleviates dfmr1-null defects, although rescue is not as complete as either early or constitutive dFMRP expression, showing a modest capacity for late-stage structural plasticity. We conclude that dFMRP predominantly acts early in synaptogenesis to modulate architecture, but that late dFMRP introduction at maturity can weakly compensate for early absence of dFMRP function.