Abstract
The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG), we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs.
Highlights
The establishment of concerted locomotor behaviors in vertebrates relies on the formation of integrated motor and sensory circuits that form between defined populations of neurons and their appropriate targets in the periphery
While wiring up the proper circuits in peripheral limbs, for example, motor axons from the spinal cord and sensory axons from the dorsal root ganglia converge in the spinal nerve
We analyzed the contribution of the axon guidance receptor Neuropilin-1 (Npn-1) to determine how axons choose their path, how well they are able to maintain their correct path, and how it influences the interactions between spinal sensory axons and motor axons
Summary
The establishment of concerted locomotor behaviors in vertebrates relies on the formation of integrated motor and sensory circuits that form between defined populations of neurons and their appropriate targets in the periphery. Several families of complementary receptor-ligand pairs that are expressed on projecting neurons and their targets and serve as axon guidance cues have been identified over the last two decades [1,2,3]. The expression of these secreted and membrane-bound factors, and their neuronal receptors, is tightly regulated, both spatially and temporally. The same family of axon guidance molecules has been implicated in pre-target segregation of axons that project to different regions of the mouse olfactory bulb. Genetic experiments revealed that these pre-target axon-axon interactions are mediated by expression of complementary amounts of Neuropilin-1 (Npn-1) and Semaphorin 3A (Sema3A) on olfactory sensory neurons and result in axonal segregation en route to their target destinations, specific and unique glomeruli in the olfactory bulb [5]
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