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Distinct cell guidance pathways control the extension of the excretory canals in C. elegans

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((Thesis)/(Dissertation)) Ph.D.
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The excretory cell is the functional equivalent to the kidney in the nematode Caenorhabditis elegans, and provides an excellent in vivo model to study directional cell migration and extension. The leading edges of the growing canals resemble neuronal growth cones in that they must be able to sense and integrate directional cues in both the dorsoventral and anteroposterior axes. The cytoskeleton regulator UNC-53/NAV2 is required for both the anterior and posterior outgrowth of several neurons, as well as the excretory cell. UNC-53 and the Abelson kinase interactor (ABI-1) appear to function cell autonomously in the excretory canals to promote outgrowth, have overlapping expression patterns, and display similar cell migration phenotypes in the canals and mechanosensory neurons. Moreover, proteins known to function with abi-1 in actin dynamics, including members of the ARP2/3 complex exhibit similar excretory cell and neuronal outgrowth defects by RNAi, suggesting that UNC-53 may act as a scaffold that links ABI-1 to the ARP2/3 complex to regulate actin cytoskeleton remodelling. Genetic analysis of putative interactors of UNC-53 suggests that UNC-53 appears to function together with UNC-71/ADAM, while the kinesin-like motor VAB-8 appears to act in a separate pathway to control the posteriorly directed excretory canal outgrowth. Analysis of putative interactors of VAB-8 suggests that VAB-8, SAX-3/ROBO, SLT-1/Slit and EVA-1 are functioning together in the outgrowth of the excretory canals. The known VAB-8 interactor, the Rac/Rho GEF UNC-73/TRIO operates in both pathways, as isoform specific alleles exhibit enhancement of the phenotype in double mutant combination with either unc-53 or vab-8. Rescue experiments suggest that a cell autonomous pathway is mediated by the Rho specific GEF domain of the UNC-73E isoform in conjunction with UNC-53, UNC-71, and ABI-1, and a cell non-autonomous pathway is mediated by the Rac specific GEF domain of the UNC-73B isoform, through partnering with VAB-8 and the receptors SAX-3 and EVA-1. Taken together, my studies indicate that the migration of the excretory canals requires two or more signaling pathways, and the guidance cues involved are also essential migration molecules functioning to guide neuronal cells and axon growth cones.
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Thesis advisor: Baillie, David
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