Early during PNS regeneration, regenerating axons emerge from the proximal nerve stump, yet whether they extend simultaneously or whether pioneering axons establish a path for follower axons remains unknown. Moreover, the molecular mechanisms underlying robust regeneration are incompletely understood. Using live imaging, we demonstrate that in zebrafish pioneering axons establish a regenerative path for follower axons. We find this process requires the synaptic receptor lrp4, and in lrp4 mutants pioneers are unaffected while follower axons frequently stall at the injury gap, providing evidence for molecular diversity between pioneering and follower axons in regeneration. We demonstrate that Lrp4 promotes regeneration through an axon extrinsic mechanism and independent of membrane anchoring and MuSK co-receptor signaling essential for synaptic development. Finally, we show that Lrp4 coordinates the realignment of denervated Schwann cells with regenerating axons, consistent with a model by which Lrp4 is repurposed to promote sustained peripheral nerve regeneration via axon-glia interactions.

中文翻译：

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突触受体Lrp4促进周围神经再生。

在PNS再生的早期，再生的轴突从近端神经残端出现，但是它们是否同时延伸或先锋轴突是否为追随者轴突建立了路径仍是未知的。此外，尚不完全了解潜在的健壮再生的分子机制。使用实时成像，我们证明了在斑马鱼中，开拓性轴突为追随者轴突建立了一条再生路径。我们发现此过程需要突触受体lrp4，并且在lrp4突变体中，先驱者不受影响，而跟随者轴突经常停滞在伤害间隙处，从而为再生过程中的开拓者和跟随者轴突之间的分子多样性提供了证据。我们证明Lrp4促进通过轴突外在机制和独立于膜锚定和MuSK共同受体信号的突触发展必不可少的再生。最后，我们显示Lrp4协调失神经的Schwann细胞与再生轴突的重排，这与Lrp4被重新用于通过轴突-胶质细胞相互作用促进持续的周围神经再生的模型相一致。