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Regulation of Axon length by RPM-1 via the DLK-1 Signaling pathway
AdvisorClark, Scott G.
Biochemistry and Molecular Biology
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The formation of neuronal connections is a complex process that involves several key steps: initiation of the axon and growth cone, axon extension, target recognition, axon growth termination and formation of synapses. Subsequently, the axon must elongate to maintain its relative position and connectivity as the animal grows longer and larger. In C. elegans, the interneuron AVG is located near the head and extends two processes: a short anteriorly directed process and a long posteriorly directed process that pioneers the ventral nerve cord and extends to the tail. To identify genes controlling axon growth and guidance, I screened for mutants with defects in the length and pattern of the AVG processes. Five mutations were isolated that caused the posteriorly directed process to extend past its normal termination site. Four mutations were alleles of the gene rpm-1, which encodes a conserved E3 ubiquitin ligase that regulates axon termination of the mechanosensory neurons and presynaptic differentiation of GABAergic neurons. One mutation was an allele of the gene fsn-1, which encodes an F-box protein that interacts and functions with RPM-1. Our results indicate that RPM-1 and FSN-1 also regulate AVG axon extension. RPM-1 acts via two pathways to control mechanosensory neuron axon growth and presynaptic differentiation. RPM-1 works via an SCF-like ubiquitin ligase complex with FSN-1 to downregulate a DLK-1 MAP kinase cascade. RPM-1 also interacts with the guanine nucleotide exchange factor GLO-4 to positively regulate the Rab GTPase GLO-1 to influence vesicular trafficking of axon guidance receptors. In AVG, we found that RPM-1 does not act via the GLO-1/GLO-4 pathway but instead acts solely through the DLK-1 MAP kinase. By analyzing rpm-1 and fsn-1 mutants at different time points, we determined that these genes do not affect the initial outgrowth of AVG during embryogenesis; rather cause it to overextend during later larval stages. Mutation of vab-8, which encodes a kinesin related protein, blocks the posteriorly directed growth of axons, including AVG. In addition, we found that mutation of the Wnts EGL-20 and LIN-44 or the Wnt receptor LIN-17 caused the AVG axon to stop before its normal termination site. fsn-1 and rpm-1 mutations were able to overcome the embryonic axon growth defects present in vab-8, lin-17, lin-44 and lin-44; egl-20 mutants and allowed AVG over extension in larval stages. These results illustrate that RPM-1 does not regulate the initial outgrowth of the posteriorly directed AVG process, but rather acts to control its length during postembryonic development. The ability of RPM-1 to influence axon length is independent of the pathways used during the initial outgrowth in embryos. Further characterization of factors and pathways involved in AVG axon extension could lead to breakthroughs in neural developmental biology for the treatment of both cognitive and motor disabilities.