Axonal defasciculation is restricted to specific branching points during regeneration of the lateral line nerve in...

Peripheral nerve regeneration requires precise selection of the appropriate targets of innervation, often in an environment that differs from that during the developmental wiring of the neural circuit. Severed axons of the zebrafish posterior lateral line nerve have the capacity to reinnervate mechanosensory hair cells clustered in neuromast organs. Regeneration represents a balance between fasciculated regrowth of the axonal bundle and defasciculation of individual axons into the epidermis where neuromasts reside. The cues that guide pathfinding during regeneration of the posterior lateral line nerve are unknown. Here we show that expression of col18a1a, which codes for the secreted heparan sulfate proteoglycan collagen XVIII, biases axonal defasciculation to specific branching points that coincide with circumscribed gaps in the epidermal boundary. We found that col18a1a is expressed by the neuromast and by a subset of Schwann cells that are located at the points of axonal defasciculation. Furthermore, we observed axon branching at inappropriate locations during nerve regeneration in col18a1a mutants. We propose a model in which a collagen XVIII-based axon-guidance cue complex attracts defasciculated axons across the epidermal basement membrane.