Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA.
Nat Commun. 2018 Jun 19;9(1):2389. doi: 10.1038/s41467-018-04806-4.
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.
在周围神经再生早期，再生轴突从近端神经残端伸出，但它们是同时延伸还是先驱轴突为后续轴突建立路径尚不清楚。此外，强大再生的分子机制还不完全清楚。通过活体成像，我们证明在斑马鱼中，先驱轴突为后续轴突建立了再生路径。我们发现这个过程需要突触受体 lrp4，在 lrp4 突变体中，先驱轴突不受影响，而后续轴突经常在损伤间隙停滞，这为再生中先驱轴突和后续轴突之间的分子多样性提供了证据。我们证明 Lrp4 通过轴突外在机制促进再生，而不依赖于膜锚定和 MuSK 共受体信号，这些对于突触发育至关重要。最后，我们表明 Lrp4 协调去神经施万细胞与再生轴突的重排，这与 Lrp4 通过轴突-胶质相互作用重新用于促进持续外周神经再生的模型一致。
