CaP growth cones do not migrate longitudinally, but extend ventrally into the periphery. Because Krox20-positive boundary cap cells have not been identified in zebrafish,caudal primary (CaP) motoneurons located just dorsal of the exit points can be used as a landmark for the exit zone ( Fig. In the zebrafish, three distinct and identifiable motor axons pioneer into the periphery through a common, mid-segmental exit point( Fig. In contrast to later steps of motor axon guidance, the cellular and molecular mechanisms by which motor axons navigate towards the segmental exit point,recognize these zones and subsequently turn ventrally to exit, are poorly understood. Elegant ablation studies have shown that boundary cap cells are important to confine motoneuron somata to the spinal cord, but that they appear to be dispensable for guiding motor growth cones( Vermeren et al., 2003). In rodents and birds, these segmental exit points are marked by Krox20 (Egr2)-positive cells - the boundary cap cells( Golding and Cohen, 1997 Niederlander and Lumsden,1996). During development, growth cones from motoneurons located within a spinal segment navigate longitudinally towards a shared segmental exit point. Although the spinal cord is externally unsegmented, motor axons exit and sensory afferents enter through distinct, segmentally organized zones along the anteroposterior axis - the motor exit points (MEPs) and the dorsal root entry zone (DREZ), respectively. We propose that axonal repulsion via Plexin A3 is a major driving force for intraspinal motor growth cone guidance.įor motor axon trajectories, one of the first guidance decisions is their longitudinal migration towards a segmental spinal cord exit point. Together, our data genetically identify the first guidance receptor required for intraspinal migration of pioneering motor axons and implicate the well-described semaphorin/plexin signaling pathway in this poorly understood process. Finally, we show that sidetracked( plexin A3) plays an additional role in motor axonal morphogenesis. Positional cloning reveals that sidetracked encodes Plexin A3, a semaphorin guidance receptor for repulsive guidance. Furthermore, we show that sidetracked acts cell autonomously in motoneurons. Misguided growth cones either orient away from the endogenous exit point, extend towards the endogenous exit point but bypass it or exit at non-segmental, ectopic locations. By single-cell labeling and time-lapse analysis we show that motoneurons with cell bodies adjacent to the segmental exit point properly exit from the spinal cord, whereas those farther away display pathfinding errors. In zebrafish sidetracked ( set) mutants, motor axons exit from the spinal cord at ectopic positions.

In contrast to later events, remarkably little is known about the molecular mechanisms underlying intraspinal motor axon guidance. One of the earliest guidance decisions for spinal cord motoneurons occurs when pools of motoneurons orient their growth cones towards a common,segmental exit point.

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