The human central nervous system is composed of 100 billion neurons interconnected into precise circuits to mediate vital functions such as perception, thought, and behavior. A critical step in development of the nervous system is the outgrowth of axons, which are necessary for long-range transfer of information. However, it is equally important for axons to terminate outgrowth once they reach a target region. Much is known about cues required for axon outgrowth. Far less is known about the molecular signals neurons utilize to appropriately terminate axon outgrowth, and how this stable state is maintained. We propose to take advantage of the simple, well-characterized nervous system of C. elegans to elucidate the molecular mechanisms underlying this critical step in neural circuit formation. Understanding this process may aid in treating neurological disorders and nervous system injuries. This proposal is relevant to the NIGMS mission to support research that increases understanding of life processes, including the field of developmental biology, that lay the foundation for advances in disease diagnosis, treatment, and prevention, to train the next generation of scientists, and to develop and increase the diversity of the scientific workforce. To understand how axon outgrowth termination is mediated, we have developed a genetically encoded marker to fluorescently label neurites of the two PHB sensory neurons. This enables us to instantly assess axon length in live animals, allowing us to rapidly discover genes mediating this fundamental process using molecular, genetic, and imaging techniques. Using this marker, we have discovered that a conserved receptor and ligand previously studied for their role in guiding axon outgrowth, SAX-3/Robo and SLT-1/Slit, have novel roles in mediating axon outgrowth termination. Our research will characterize the mechanism of this new modality and define the pathway by which it is executed.
Our specific aims are to: 1) characterize the role of SAX-3/Robo and SLT-1/Slit in axon outgrowth termination, 2) investigate the pathway by which SAX-3/Robo mediates axon outgrowth termination, and 3) characterize the role of SAX-3/Robo pathway members. The PI's short-term developmental objects are to 1) perform experiments described in this proposal, 2) present the findings at region, national, and international scientific meeting, and 3) publish manuscripts in leading, peer-reviewed journals. In the long-term, the PI's goal is to further the understanding of how neural circuits are formed and function in order to aid in the development of treatments for neurological disorders and spinal cord injuries. This MBRS SC3 will fund the research of approximately 16 undergraduates and 4 M.S. students over four years, including many underrepresented trainees at San Jos? State University, a primarily undergraduate and Masters-level university committed to training under-represented students. Undergraduates will perform the majority of the proposed work, with mentoring from M.S. students, a technician, and the PI. This funding would allow the PI to continue to develop a strong track record in research in order to secure future non-SCORE funding.

Public Health Relevance

During development, neurons must extend their axons to appropriate target regions and, once there, terminate extension. We seek to identify the molecular mechanisms that underlie axon outgrowth termination, a critical step in neural circuit formation. Understanding these mechanisms may be important for developing therapeutics to treat neurological disorders and injuries to the nervous system.

National Institute of Health (NIH)
Research Continuance Award (SC3)
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Special Emphasis Panel (ZGM1)
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Okita, Richard T
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San Jose State University
Schools of Arts and Sciences
San Jose
United States
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Barsi-Rhyne, Benjamin J; Miller, Kristine M; Vargas, Christopher T et al. (2013) Kinesin-1 acts with netrin and DCC to maintain sensory neuron position in Caenorhabditis elegans. Genetics 194:175-87
Smith, Cody J; Watson, Joseph D; VanHoven, Miri K et al. (2012) Netrin (UNC-6) mediates dendritic self-avoidance. Nat Neurosci 15:731-7
Park, Joori; Knezevich, Philip Louis; Wung, William et al. (2011) A conserved juxtacrine signal regulates synaptic partner recognition in Caenorhabditis elegans. Neural Dev 6:28