At the neuromuscular junction (NMJ), lipoprotein‐related receptor 4 (LRP4) mediates agrin‐induced MuSK phosphorylation that leads to clustering of acetylcholine receptors (AChRs) in the postsynaptic region of the skeletal muscle. Additionally, the ectodomain of LRP4 is necessary for differentiation of the presynaptic nerve terminal. However, the molecules regulating LRP4 have not been fully elucidated yet. Here, we show that the CT domain of connective tissue growth factor (CTGF/CCN2) directly binds to the third beta‐propeller domain of LRP4. CTGF/CCN2 enhances the binding of LRP4 to MuSK and facilitates the localization of LRP4 on the plasma membrane. CTGF/CCN2 enhances agrin‐induced MuSK phosphorylation and AChR clustering in cultured myotubes. Ctgf‐deficient mouse embryos (Ctgf ^−/−) have small AChR clusters and abnormal dispersion of synaptic vesicles along the motor axon. Ultrastructurally, the presynaptic nerve terminals have reduced numbers of active zones and mitochondria. Functionally, Ctgf ^−/− embryos exhibit impaired NMJ signal transmission. These results indicate that CTGF/CCN2 interacts with LRP4 to facilitate clustering of AChRs at the motor endplate and the maturation of the nerve terminal.

中文翻译：

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CTGF/CCN2 促进 LRP4 介导的胚胎神经肌肉接头的形成。

在神经肌肉接头 (NMJ)，脂蛋白相关受体 4 (LRP4) 介导集聚蛋白诱导的 MuSK 磷酸化，导致骨骼肌突触后区域的乙酰胆碱受体 (AChR) 聚集。此外，LRP4 的胞外域是突触前神经末梢分化所必需的。然而，调节 LRP4 的分子尚未完全阐明。在这里，我们展示了结缔组织生长因子 (CTGF/CCN2) 的 CT 结构域直接与 LRP4 的第三个 β-螺旋桨结构域结合。CTGF/CCN2 增强 LRP4 与 MuSK 的结合并促进 LRP4 在质膜上的定位。CTGF/CCN2 增强培养的肌管中集聚蛋白诱导的 MuSK 磷酸化和 AChR 聚集。Ctgf 缺陷小鼠胚胎 ( Ctgf ^-/-) 有小的 AChR 簇和突触小泡沿运动轴突的异常分散。超微结构上，突触前神经末梢的活动区和线粒体数量减少。在功能上，Ctgf ^-/-胚胎表现出 NMJ 信号传输受损。这些结果表明 CTGF/CCN2 与 LRP4 相互作用以促进 AChR 在运动终板的聚集和神经末梢的成熟。