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Pioneers and followers in the ventral nerve cord of Caenorhabditis elegans: characterization of follower axon guidance defects and motor circuit function in mutants with pioneer guidance defects.

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(Thesis) Ph.D.
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During nervous system development, axons navigate complex environments to reach synaptic targets. Early extending axons must interact with guidance cues in the surrounding tissue, while later extending axons can interact directly with earlier "pioneering" axons, "following" their path. In Caenorhabditis elegans, the AVG neuron pioneers the right axon tract of the ventral nerve cord. We previously found that aex-3, a rab-3 guanine nucleotide exchange factor, is essential for AVG axon navigation in a nid-1 mutant background and that aex-3 might be involved in trafficking of UNC-5, a receptor for the guidance cue UNC-6/netrin. Here, we further expand this pathway: ccd-5 is a putative cdk-5 binding partner that shares a genetic pathway with rab-3, while mutations in the IgCAMs wrk-1 or rig-5 suppress axon guidance defects in cdk-5 and ccd-5 mutants respectively. wrk-1 and rig-5 defects are additive, suggesting that they act in parallel to regulate axon guidance. rig-5 shares a pathway with fellow IgCAM rig-6, and wrk-1 shares a pathway with the ephrin receptor vab-1. Null mutations in a nid-1 mutant background result in highly penetrant axon navigation defects. Navigation defects of follower interneuron and motor neuron axons correlate with AVG pioneer axon defects, suggesting that mutations in this pathway mostly affect pioneer axon navigation and follower axon defects are largely a secondary consequence of pioneer navigation defects. To determine whether these navigation defects impact nervous system function, we assessed baseline locomotion, responsiveness to mechanosensory stimuli, and mechanosensory habituation in rig-5 nid-1 and ccd-5 nid-1 mutant animals. We observed only mild defects in some measurements of tap response and habituation. Further investigation uncovered two subpopulations each strain with two discrete response durations. Control animals habituated in part by shifting from a long-duration response type to a short-duration response type. Both rig-5 nid-1 and ccd-5 nid-1 double mutants have defects in this shift. These results suggest that guidance defects of axons in the motor circuit do not necessarily lead to major movement or behavioural defects but impact more complex behavioural modulation.
180 pages.
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Thesis advisor: Hutter, Harald
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