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Cells. 2019 Nov 16;8(11):1448. doi: 10.3390/cells8111448.
The vertebrate skeletal neuromuscular junction (NMJ) has long served as a model system for studying synapse structure, function, and development. Over the last several decades, a neuron-specific isoform of agrin, a heparan sulfate proteoglycan, has been identified as playing a central role in synapse formation at all vertebrate skeletal neuromuscular synapses. While agrin was initially postulated to be the inductive molecule that initiates synaptogenesis, this model has been modified in response to work showing that postsynaptic differentiation can develop in the absence of innervation, and that synapses can form in transgenic mice in which the agrin gene is ablated. In place of a unitary mechanism for neuromuscular synapse formation, studies in both mice and zebrafish have led to the proposal that two mechanisms mediate synaptogenesis, with some synapses being induced by nerve contact while others involve the incorporation of prepatterned postsynaptic structures. Moreover, the current model also proposes that agrin can serve two functions, to induce synaptogenesis and to stabilize new synapses, once these are formed. This review examines the evidence for these propositions, and concludes that it remains possible that a single molecular mechanism mediates synaptogenesis at all NMJs, and that agrin acts as a stabilizer, while its role as inducer is open to question. Moreover, if agrin does not act to initiate synaptogenesis, it follows that as yet uncharacterized molecular interactions are required to play this essential inductive role. Several alternatives to agrin for this function are suggested, including focal pericellular proteolysis and integrin signaling, but all require experimental validation.
脊椎动物骨骼神经肌肉接头 (NMJ) 长期以来一直是研究突触结构、功能和发育的模型系统。在过去的几十年中，一种神经特异性的聚集素 (一种硫酸乙酰肝素蛋白聚糖) 同工型被确定在所有脊椎动物骨骼神经肌肉突触的形成中起着核心作用。虽然聚集素最初被假定为启动突触发生的诱导分子，但这个模型已经根据研究进行了修改，这些研究表明，在没有神经支配的情况下，突触后分化也可以发育，并且在聚集素基因缺失的转基因小鼠中，突触也可以形成。在神经肌肉突触形成的单一机制中，在小鼠和斑马鱼中的研究导致了两种机制介导突触发生的提议，一些突触是由神经接触诱导的，而另一些则涉及预先形成的突触后结构的整合。此外，目前的模型还提出，聚集素可以发挥两种功能，即在形成后诱导突触发生和稳定新的突触。这篇综述审查了这些命题的证据，并得出结论，仍然有可能是单一的分子机制介导所有 NMJs 的突触发生，并且聚集素作为稳定剂起作用，而其作为诱导物的作用则存在疑问。此外，如果聚集素不参与启动突触发生，那么就需要尚未被表征的分子相互作用来发挥这种必需的诱导作用。提出了几种替代聚集素的功能的替代物，包括局灶性细胞周蛋白水解和整合素信号转导，但所有这些都需要实验验证。
