As described in my book on nerve regeneration, axons of the peripheral nervous system (PNS) have a good ability to regenerate after injury. However, for functional recovery of mobility, it is crucial that motor axons reconnect with their original muscle targets. In mammals, targeting errors, i.e., incorrect re-innervation of the muscle fibers, are unfortunately quite common and can cause long-term deficits. There is a lack of spatial cues to guide the growing axons to their original targets.
In recent work by Lauren Walker and colleagues from the University of Pennsylvania (Philadelphia, USA), the specific regeneration of axons located at the base of the zebrafish pectoral fin was examined in detail. In this model, the transparency of the fin allows for high-resolution imaging to study axon growth precisely and in real time. This essentially corresponds to the regeneration of plexus nerves in our brachial plexus, but is more specific and therefore more successful.
After selectively marking the neural processes leading to the fin muscles, the authors found that motor axons from three nerves intermingle in the fin's plexus and then target their original muscle areas with high accuracy, restoring functionality. This regeneration process includes not only axon growth but also the selective retraction of misguided processes (pruning). Previous work had already hypothesized how axon growth could be controlled during regeneration, but the molecular and cellular mechanisms enabling correct navigation through a plexus are still largely unknown. It has been long suspected that denervated (reactive) Schwann cells, which upregulate trophic factors and form tracks (so-called Büngner bands) along which regenerating axons can grow, play a crucial role in this process.
To connect to their correct muscle fibers, zebrafish fin motor axons navigate along several molecular signposts made by Schwann cells, as their removal prevents specific regeneration. Initially, the axons sort at the plexus nerves between the muscles and then choose a path at subsequent choice points within the musculature to contact the functionally appropriate muscle fibers. In zebrafish, regenerating axons are guided by Schwann cells that upregulate a specific collagen (col4a5) and thereby mediate axonal growth decisions between dorsal and ventral motor nerves in the trunk. The molecular signals expressed by Schwann cells in the dorsal plexus of the fin are not yet known. They could involve polysialic acid or the cell adhesion molecule L1, as well as EphrinA-EphA4-, GDNF/Ret-, or Sema3A-Npn-1-dependent signaling pathways. Whether these are also required in the PNS of mammals for specific nerve regeneration remains to be investigated.
Taken together, the nerve plexus of the pectoral fin makes the zebrafish an ideal model system, due to its genetic tractability and optical transparency, as well as the ability to analyze fin movements as a measure of successful regeneration, to thoroughly investigate the mechanisms of target-selective axon regeneration in the peripheral nervous system.
Reference:
Walker LJ, Guevara C, Kawakami K, Granato M (2023) Target-selective vertebrate motor axon regeneration depends on interaction with glial cells at a peripheral nerve plexus. PLOS Biology 21:e3002223
Image credit: iStock/Allexxandar
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