One of the unique features of neurons that make learning and memory possible is their ability to alter their shape to make contact with other neurons. The ability of neurons to alter their shape to form these contacts is dependent on the regulation of the cytoskeleton ? a highly dynamic network of intracellular filaments that provide a function analogous to bones in the human body. Because of its role in regulating neuronal shape, the cytoskeleton is believed to play a critical role in several nervous system disorders, such as Alzheimer?s disease. In spite of the importance of the cytoskeleton in neurons, it is unclear whether all of the cytoskeletal filaments in neurons have been identified. The PI has conducted a genome wide-screen for novel filament-forming proteins. This screen identified one protein that forms filaments in the cellular extensions called axons that connect neurons to each other suggesting that this protein has a cytoskeletal function. Surprisingly, this filament-forming protein, CTP synthase, is also responsible for synthesizing nucleotides, the building blocks of DNA, arguing that CTP synthase is an unusual protein with two distinct functions. The goal of this proposal is to use powerful genetic approaches to identify mutant forms of CTP synthase that are selectively defective in the ability to form filaments. These mutants will be used to determine if the ability of CTP synthase to form filaments is necessary for neurons to form functional connections. The identification of a novel component of the neuronal cytoskeleton will have broad implications for our understanding of how neuronal connections are formed and will open a new area for cell biological research. Furthermore, graduate and undergraduate researchers will be integrated into all aspects of the project providing an opportunity to train the next generation of scientists in a cutting-edge area of neuroscience.
