Intrinsic positional memory guides target-specific axon regeneration in the zebrafish vagus nerve.

Abstract

Regeneration after peripheral nerve damage requires that axons re-grow to the correct target tissues in a process called target-specific regeneration. While much is known about the mechanisms that promote axon re-growth, re-growing axons often fail to reach the correct targets, resulting in impaired nerve function. We know very little about how axons achieve target-specific regeneration, particularly in branched nerves that require distinct targeting decisions at branch points. The zebrafish vagus motor nerve is a branched nerve with a well-defined topographic organization. Here, we track regeneration of individual vagus axons after whole-nerve laser severing and find a robust capacity for target-specific, functional regrowth. We then develop a new single-cell chimera injury model for precise manipulation of axon-environment interactions and find that 1) the guidance mechanism used during regeneration is distinct from the nerve s developmental guidance mechanism, 2) target selection is specified by neurons intrinsic memory of their position within the brain, and 3) targeting to a branch requires its pre-existing innervation. This work establishes the zebrafish vagus nerve as a tractable regeneration model and reveals the mechanistic basis of target-specific regeneration.