Molecular Mechanisms of Neural Circuit Formation

描述（由申请人提供）：人类中枢神经系统由1000亿个神经元组成，这些神经元相互连接成精确的电路，调节感知、思维和行为等重要功能。神经系统发育的一个关键步骤是轴突的生长，这是远程信息传递所必需的。然而，轴突到达目标区域后终止生长也同样重要。关于轴突生长所需的线索，我们知道得很多。对于神经元利用分子信号来适当地终止轴突生长，以及如何维持这种稳定状态，人们知之甚少。我们建议利用秀丽隐杆线虫的简单、特征明确的神经系统来阐明神经回路形成这一关键步骤的分子机制。了解这一过程可能有助于治疗神经系统疾病和神经系统损伤。这一建议与NIGMS的使命相关，即支持能够增进对生命过程的理解的研究，包括发育生物学领域，为疾病诊断、治疗和预防的进步奠定基础，培养下一代科学家，发展和增加科学劳动力的多样性。来

DESCRIPTION (provided by applicant): 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.