Elucidating the mechanisms that control the pathfinding of dorsal spinal commissural axons to their brain targets
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The proper function of the mature nervous system is critically dependent on the formation of stereotypical neural circuits during development. Dorsal spinal commissural neurons comprise a major class of ascending projection neurons, which project over long distances along the anterior-posterior axis of the developing central nervous system to transmit sensory information to various parts of the brain. Despite significant progress in elucidating the mechanisms that direct pre-crossing commissural axons to the ventral midline of the spinal cord, we do not have a clear understanding of the contralateral navigational program, which guides decussated axons into appropriate longitudinal tracts and to their poorly characterized synaptic targets. Here, I elucidate a novel molecular mechanism that guides spinal commissural axons into longitudinally oriented ascending tracts in chick and mouse embryos. Furthermore, I identify the central targets of d1 and d2 genetically distinct dorsal spinal commissural neurons/axons, and show that the targeting of these axons is dependent on their positioning in particular longitudinally projecting tracts within the spinal cord marginal zone. Specifically, by employing gain- and loss-of-function manipulations, I show that Robo receptor-mediated inhibition of the N-cadherin cell adhesion molecule guides post-crossing spinal commissural axons into the lateral funiculus of the marginal zone. I then demonstrate that the positioning of decussated spinal commissural axons into the lateral funiculus via Robo-mediated inhibition of N-cadherin is required for d1 and d2 axons to project to the cerebellum and, thereby, spinocerebellar tract formation. Collectively, these results support a model in which the pre-sorting and proper positioning of ascending longitudinal spinal axon tracts within the vertebrate spinal cord is required for their targeting in the brain.