RUI: Physics of Cytoskeletal Organization in Neural Development

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Neurons are specialized cells that transmit electrical impulses to control heart rate, movement, and higher brain function. A complex network of neurons must be "wired" properly to support the spatial and temporal coordination of neural signals. During nervous system development, neurons project fibers called axons, which undergo directed growth to form connections with other cells. A network of dynamic protein filaments called the cytoskeleton facilitates several distinct mechanical functions underlying axonal outgrowth and development. The goal of this project is to apply computational models to better understand how forces and movements in the cytoskeleton mediate neural development and function. The project will provide training to a diverse group of undergraduate students at a regional comprehensive university that is approximately 95% undergraduate, 40% first-generation college students, and 20% from underrepresented minorities. The proposed project will build on the impact of existing university programs that provide research opportunities for students from underrepresented groups. Undergraduate students involved in the research will have the opportunity to become immersed in basic research full time for two months during the summer (10-12 students over the funding period). The PI has developed several novel courses at the boundary of physics and biology, and has developed and led interdisciplinary science outreach workshops designed to engage low-income students and other underrepresented groups in STEM fields.The PI will develop agent-based computational models to investigate cytoskeletal organization and mechanical function in developing neurons, with particular emphasis on two distinct neuronal compartments: (1) a slender fiber called an axon, along which neural impulses are conducted from the cell body to other cells; and (2) a sensory-motile structure at the tips of axons called a growth cone, which guides axonal outgrowth during development or regeneration. These regions of the neuron both contain many of the same cytoskeletal components, but in each context these molecular components are repurposed for functionally distinct mechanical tasks. Novel mechanical models will be developed to investigate emergent behavior that arises on a systems level from the molecular scale interaction of the parts. The models will be tested and refined in close collaboration with experimental colleagues, and model predictions will guide the design of new experiments. The project will address fundamental mechanistic questions about developing neurons, including: How do axons grow in the correct direction during embryogenesis to form the appropriate connections with other cells? How do growing axons develop and maintain an organized internal structure capable of facilitating directed intracellular transport of neurotransmitters and other cellular vesicles? When cytoskeletal organization in axons is disrupted due to disease or injury, what mechanisms may contribute to axonal repair? Specific objectives are: (1) Investigate how cytoskeletal filaments and growth cone substrate adhesion are coordinated to facilitate growth cone steering in response to chemical guidance cues; (2) Investigate how developing axons establish and maintain an organized array of polar microtubule filaments that is essential to support healthy nervous system function.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.