LAR Receptor Tyrosine Phosphatases and HSPGs Guide Peripheral Sensory Axons to the Skin

Background: Peripheral axons of somatosensory neurons innervate the skin early in development to detect touch stimuli. Embryological experiments had suggested that the skin produces guidance cues that attract sensory axons, but neither the attractants nor their neuronal receptors had previously been identified. Results: To investigate peripheral axon navigation to the skin, we combined live imaging of developing zebrafish Rohon-Beard (RB) neurons with molecular loss-of-function manipulations. Simultaneously knocking down two members of the leukocyte antigen-related (LAR) family of receptor tyrosine phosphatases expressed in RB neurons, or inhibiting their function with dominant-negative proteins, misrouted peripheral axons to internal tissues. Time-lapse imaging indicated that peripheral axon guidance, rather than outgrowth or maintenance, was defective in LAR-deficient neurons. Peripheral axons displayed a similar nnisrouting phenotype in mutants defective in heparan sulfate proteoglycan (HSPG) production and avoided regions in which HSPGs were locally degraded. Conclusions: HSPGs and LAR family receptors are required for sensory axon guidance to the skin. Together, our results support a model in which peripheral HSPGs are attractive ligands for LAR receptors on RB neurons.