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 regenerating axons selectively defasciculate through distinct gaps in the epidermal boundary layer. We found that the gene col18a1a, which encodes the secreted heparan sulfate proteoglycan collagen XVIII, is expressed by the neuromast and by a subset of Schwann cells that are located at the points of axonal defasciculation. Furthermore, we observed aberrant axonal branching at inappropriate locations during nerve regeneration in col18a1a mutants. We propose a model in which collagen XVIII patterns the basement membrane to affect the precision of axonal navigation.