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首页> 外文期刊>Current Biology: CB >A conserved role for Drosophila Neuroglian and human L1-CAM in central-synapse formation
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A conserved role for Drosophila Neuroglian and human L1-CAM in central-synapse formation

机译：果蝇神经胶质和人L1-CAM在中央突触形成中的保守作用。

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BACKGROUND: Drosophila Neuroglian (Nrg) and its vertebrate homolog L1-CAM are cell-adhesion molecules (CAM) that have been well studied in early developmental processes. Mutations in the human gene result in a broad spectrum of phenotypes (the CRASH-syndrome) that include devastating neurological disorders such as spasticity and mental retardation. Although the role of L1-CAMs in neurite extension and axon pathfinding has been extensively studied, much less is known about their role in synapse formation. RESULTS: We found that a single extracellular missense mutation in nrg(849) mutants disrupted the physiological function of a central synapse in Drosophila. The identified giant neuron in nrg(849) mutants made a synaptic terminal on the appropriate target, but ultrastructural analysis revealed in the synaptic terminal a dramatic microtubule reduction, which was likely to be the cause for disrupted active zones. Our results reveal that tyrosine phosphorylation of the intracellular ankyrin binding motif was reduced in mutants, and cell-autonomous rescue experiments demonstrated the indispensability of this tyrosine in giant-synapse formation. We also show that this function in giant-synapse formation was conserved in human L1-CAM but neither in human L1-CAM with a pathological missense mutation nor in two isoforms of the paralogs NrCAM and Neurofascin. CONCLUSIONS: We conclude that Nrg has a function in synapse formation by organizing microtubules in the synaptic terminal. This novel synaptic function is conserved in human L1-CAM but is not common to all L1-type proteins. Finally, our findings suggest that some aspects of L1-CAM-related neurological disorders in humans may result from a disruption in synapse formation rather than in axon pathfinding.
机译：背景：果蝇神经胶质细胞（Nrg）及其脊椎动物同系物L1-CAM是细胞粘附分子（CAM），在早期发育过程中已得到充分研究。人类基因的突变会导致多种表型（CRASH综合征），包括破坏性神经系统疾病，例如痉挛和智力低下。尽管已经广泛研究了L1-CAM在神经突延伸和轴突寻路中的作用，但人们对它们在突触形成中的作用知之甚少。结果：我们发现nrg（849）突变体中的单个胞外错义突变破坏了果蝇中央突触的生理功能。在nrg（849）突变体中识别出的巨型神经元在适当的靶标上形成了一个突触末端，但超微结构分析显示，在突触末端显着减少了微管，这很可能是活动区域被破坏的原因。我们的结果表明，胞内锚蛋白结合基序的酪氨酸磷酸化在突变体中减少，并且细胞自主抢救实验证明了这种酪氨酸在巨突触形成中不可或缺。我们还表明，这种功能在巨突触形成中在人L1-CAM中是保守的，但在具有病理性错义突变的人L1-CAM中或在旁系同源物NrCAM和Neurofascin的两个同工型中都没有。结论：我们认为Nrg通过在突触末端组织微管而在突触形成中具有功能。这种新的突触功能在人类L1-CAM中是保守的，但并非对所有L1型蛋白都是共有的。最后，我们的发现表明，人类与L1-CAM相关的神经系统疾病的某些方面可能是由于突触形成的破坏而不是轴突寻路引起的。

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