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UNC-5 (UNC5) Regulates UNC-40 Localization, Cell Migration, Axon Protrusion and Branching During C. Elegans Neuronal Development

by
Gerard Limerick
B.S., Oakwood University - 2007

Thesis Advisors: William G. Wadsworth, Ph.D.
Graduate Program in Biochemistry

Robert Wood Johnson Medical School
Room V-10
Piscataway

Tuesday, May 6, 2014
10:00 a.m.


Abstract

For many decades, spinal cord injury (SCI) has been an intractable problem in our society. Since there are very few treatment options for SCI, most physicians focus on reducing clinical sequelae from the injury. In order to develop more therapies for treating SCI, we must understand more about the fundamental principles governing the development of the nervous system. One basic question about nervous system development is, “How do axons navigate to their proper synaptic partner?” A start to answering this question has come through the identification of a family of proteins known as axon guidance cues. Axon guidance cues are responsible for directing axons to their synaptic partners. In our lab, we use the nematode Caenorhabditis elegans to study the axon guidance cue UNC-6 (netrin) and its receptors UNC-5 (UNC5) and UNC-40 (DCC). Axons expressing UNC-40 are guided towards the source of UNC-6, while axons expressing UNC-5 and UNC-40 are guided away from the source of UNC-6.
Here, we find that the UNC-5 (UNC5) receptor and the cytoskeletal binding protein UNC-53 (NAV2) regulate the induction of UNC-40 localization by UNC-6. We find that UNC-5 helps to regulate the timing of axon protrusion from HSN. We also find that UNC-5 helps to regulate the migration of the HSN cell body. We report that UNC-5 works with MIG-15, a TNIK (Traf- and Nck-Interacting Kinase)/NIK (NCK-Interacting Kinase), to regulate branching at the nerve ring. Lastly, an ectopic branching phenotype induced by a variant of UNC-6 that lacks the C terminus is suppressed in an unc-5 background. We hold that the ability of UNC-5 to regulate UNC-40 localization allows UNC-5 to regulate various neurodevelopmental processes, including, but not limited to, cell migration, axon protrusion and axon branching. These studies contribute to our understanding of UNC-6 signaling and help provide a new paradigm for axon guidance.


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