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首页> 外文期刊>Frontiers in Molecular Neuroscience >Fragile X Mental Retardation Protein Regulates Activity-Dependent Membrane Trafficking and Trans-Synaptic Signaling Mediating Synaptic Remodeling
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Fragile X Mental Retardation Protein Regulates Activity-Dependent Membrane Trafficking and Trans-Synaptic Signaling Mediating Synaptic Remodeling

机译：脆弱的X智力迟缓蛋白调节活动依赖的膜运输和 Trans -突触信号介导的突触重塑。

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Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. The disease arises through loss of fragile X mental retardation protein (FMRP), which normally exhibits peak expression levels in early-use critical periods, and is required for activity-dependent synaptic remodeling during this transient developmental window. FMRP canonically binds mRNA to repress protein translation, with targets that regulate cytoskeleton dynamics, membrane trafficking, and trans -synaptic signaling. We focus here on recent advances emerging in these three areas from the Drosophila disease model. In the well-characterized central brain mushroom body (MB) olfactory learning/memory circuit, FMRP is required for activity-dependent synaptic remodeling of projection neurons innervating the MB calyx, with function tightly restricted to an early-use critical period. FMRP loss is phenocopied by conditional removal of FMRP only during this critical period, and rescued by FMRP conditional expression only during this critical period. Consistent with FXS hyperexcitation, FMRP loss defects are phenocopied by heightened sensory experience and targeted optogenetic hyperexcitation during this critical period. FMRP binds mRNA encoding Drosophila ESCRTIII core component Shrub (human CHMP4 homolog) to restrict Shrub translation in an activity-dependent mechanism only during this same critical period. Shrub mediates endosomal membrane trafficking, and perturbing Shrub expression is known to interfere with neuronal process pruning. Consistently, FMRP loss and Shrub overexpression targeted to projection neurons similarly causes endosomal membrane trafficking defects within synaptic boutons, and genetic reduction of Shrub strikingly rescues Drosophila FXS model defects. In parallel work on the well-characterized giant fiber (GF) circuit, FMRP limits iontophoretic dye loading into central interneurons, demonstrating an FMRP role controlling core neuronal properties through the activity-dependent repression of translation. In the well-characterized Drosophila neuromuscular junction (NMJ) model, developmental synaptogenesis and activity-dependent synaptic remodeling both require extracellular matrix metalloproteinase (MMP) enzymes interacting with the heparan sulfate proteoglycan (HSPG) glypican dally-like protein (Dlp) to restrict trans -synaptic Wnt signaling, with FXS synaptogenic defects alleviated by both MMP and HSPG reduction. This new mechanistic axis spanning from activity to FMRP to HSPG-dependent MMP regulation modulates activity-dependent synaptogenesis. We discuss future directions for these mechanisms, and intersecting research priorities for FMRP in glial and signaling interactions.
机译：脆弱X综合征（FXS）是自闭症和智力残疾的主要单基因病因。该病是由于脆弱的X智力障碍蛋白（FMRP）的丧失而引起的，该蛋白通常在早期使用的关键时期表现出峰值表达水平，并且在此短暂的发育窗口期间需要进行依赖于活性的突触重塑。 FMRP典型地结合mRNA以抑制蛋白质翻译，其靶标可调控细胞骨架动力学，膜运输和反突触信号传导。在这里，我们重点介绍果蝇疾病模型在这三个领域中出现的最新进展。在特征明确的中枢脑蘑菇体（MB）嗅觉学习/记忆回路中，FMRP是支配MB萼的投射神经元的活动依赖型突触重塑的功能，其功能严格限制在早期使用关键时期。仅在此关键时期通过有条件地去除FMRP来表现FMRP的丧失，而仅在此关键时期通过FMRP条件表达来挽救。与FXS过度兴奋相一致，在此关键时期，通过增强的感官体验和定向的光遗传学过度兴奋来显式表现出FMRP缺失缺陷。 FMRP仅在相同的关键时期结合编码果蝇ESCRTIII核心成分灌木（人类CHMP4同源物）的mRNA，以活动依赖的机制限制灌木的翻译。灌木介导内体膜运输，并且扰动灌木表达已知干扰神经元过程修剪。一致地，针对投射神经元的FMRP损失和灌木过表达类似地导致突触钮扣内的内体膜运输缺陷，并且灌木的遗传减少显着挽救了果蝇FXS模型缺陷。在表征良好的巨型纤维（GF）电路的并行工作中，FMRP限制了离子电渗染料向中央中间神经元的负载，从而证明了FMRP通过依赖于活性的翻译抑制作用来控制核心神经元特性。在功能完善的果蝇神经肌肉接头（NMJ）模型中，发育突触形成和活动依赖性突触重塑都需要胞外基质金属蛋白酶（MMP）酶与硫酸乙酰肝素蛋白聚糖（HSPG）甘草酸二聚体样蛋白（Dlp）相互作用来限制反式-突触Wnt信号，通过减少MMP和HSPG减轻FXS突触缺陷。从活性到FMRP，再到HSPG依赖的MMP调节，这一新的机械轴调节了活性依赖的突触形成。我们讨论了这些机制的未来方向，并探讨了胶质和信号相互作用中FMRP的研究重点。

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