Elucidating the mechanisms that control the pathfinding of dorsal spinal commissural axons to their brain targets

Abstract

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.