AXON GUIDANCE IN THE SPINAL CORD

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The goal of this work is to determine the cellular and molecular events that underlie the guidance of axons within the developing CNS. The development of the earliest commissural axon trajectory in the embryonic rat spinal cord provides an accessible model system in which to study the cues that guide CNS axonal projections. Commissural axons initially project circumferentially, away from the dorsal midline and close to the lateral edge of the spinal cord. The path of this axonal migration may be regulated by signals from the dorsal midline structure, the roof plate, and constrained laterally by an extracellular matrix component, the laminin-heparan sulphate proteoglycan complex. Commissural axons extend towards and across the ventral midline but then abruptly change their direction of extension, turning through 90 degrees to project longitudinally and rostrally within the ventral funiculus. The axonal turn occurs coincident with the contralateral boundary of a group of cells, known as the floor plate, that spans the ventral midline. The turn is disrupted in embryos in which the floor plate is absent, suggesting that navigational information is associated with the floor plate itself. However, in addition to floor plate cells and their underlying basal lamina, two other potential sources of guidance cues are: axons crossing from the contralateral side and neuroepithelium lateral to the floor plate. The cue that directs longitudinal growth in a rostral direction may be localized within the spinal cord or may emanate from a supraspinal source. In vitro preparations of spinal cord have been established that permit visualization and experimental perturbation of the commissural projection as it develops. Ectopic presentation and selective ablation of distinct cell types and antibody perturbation of cell surface molecules will be used to examine whether the roof plate regulates the direction of circumferential growth, which of the cells contacted by commissural growth cones are required for pathfinding at the midline and whether the functions of these cell types are mediated by any of several identified molecules. These experiments will provide information about the range of cues that together shape an axonal projection and the role of intermediate targets in axon guidance. Despite the prevalence and importance of projection paths in the CNS there is currently no information on the cues that are likely to operate initially to direct longitudinal growth. The experiments described above therefore have important implications for our understanding of the development of projection pathways throughout the CNS.