Abstract
Nervous system function requires that neurons within neural circuits are connected together precisely. These connections form during the process of axon guidance whereby each neuron extends an axon that migrates, often large distances, through a complex environment to reach its synaptic target. This task can be simplified by utilising intermediate targets to divide the route into smaller sections. This requires that axons adapt their behaviour as they migrate towards and away from intermediate targets. In the central nervous system the midline acts as an intermediate target for commissural axons. In Drosophila commissural axons switch from attraction towards to extension away from the midline by regulating the levels of the Roundabout receptor on their cell surface. This is achieved by Commissureless which directs Roundabout to an intracellular compartment in the soma prior to reaching the midline. Once across the midline Roundabout is allowed to reach the surface and acts as a receptor for the repellent ligand Slit that is secreted by cells at the midline. Here we investigated candidate intracellular mechanisms that may facilitate the intracellular targeting of Commissureless and Roundabout within the soma of commissural neurons. Using modified forms of Commissureless or Rabs we show that neither ubiquitination nor Rab activity are necessary for the intracellular targeting of Commissureless. In addition we reveal that axon outgrowth of many populations of neurons within the Drosophila central nervous system is also independent of Rab activity.
Highlights
During the development of the central nervous system a large number of neurons must form a precise pattern of connections
Neurons have to extend over a considerable distance and this process is facilitated by the neuron taking a series of smaller trajectories between intermediate targets or guideposts along their route
Mutation of the Nedd4 binding site (Comm2AY) in which the PPCY and LPSY motifs are mutated to AY or replacement of all the intracellular lysines in Comm with arginine (Comm10K-.R) to remove all the sites available for ubiquitin addition, diverts localisation of Comm to the cell surface of S2 cells and muscles [9,13]
Summary
During the development of the central nervous system a large number of neurons must form a precise pattern of connections. On reaching an intermediate target the axon must adapt its behaviour in order to leave and continue extending along its path. The majority of CNS axons are commissural axons which project from one side of the CNS to join a longitudinal tract on the opposite (contralateral) side, while a smaller number of axons never cross and remain on their own (ipsilateral) side. Those axons that cross the midline do so only once and do not re-cross. This suggests that shortly after the axon has reached the midline it adapts its response to the guidance cues it experiences such that it is no longer attracted to the midline
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