? The nervous system is composed of a vast number of neurons that vary dramatically in size and shape. Neurons are highly polarized cells with distinct subcellular compartments, including one or more dendritic processes arising from the cell body and a single, extended axon. Elucidating the mechanisms that control neuronal polarity and dendritic development is of critical importance for understanding the development and plasticity of a functional nervous system. In addition, alternations in the number of dendritic branches and dendritic spines are often found in patients with neurological disorders, such as fragile X syndrome. Fragile X syndrome is the most common form of inherited mental retardation in humans, with an estimated incidence of 1 in 4000 males and 1 in 8000 females. The disorder is caused by the loss of the fragile X mental retardation 1 (fmr1) gene activity. FMR1 is an RNA-binding protein that contains two ribonucleoprotein K homology domains (KH domains) and an arginine- and glycine-rich domain (RGG box). The physiological function of FMR1 in neural development remains largely unknown. The long-term goal of this laboratory is to understand the molecular mechanisms underlying dendritic outgrowth, branching, and remodeling during development. The peripheral nervous system (PNS) of the fruitfly Drosophila is an ideal model system for these studies. PNS neurons can be individually identified, and their dendritic morphology can be studied in real time in living animals. A large number of genes identified in PNS also affect dendritic development of central nervous system (CNS) neurons. In addition, the Drosophila model allows powerful genetic and molecular manipulations. Recently, we have generated specific mutations in the Drosophila fmr1 (dfmr1) gene. Our preliminary studies indicate that dfmr1 mutations primarily affect the formation of higher-order dendritic branches. In this proposal, we will carry out a series of experiments to further understand how FMR1 controls dendritic development. Specially, (1) we will further characterize the dendritic overextension phenotype caused by dfmr1 mutations, (2) we will investigate how dFMR1 functions at the mechanistic level, and (3) we will use genetic approaches to identify other proteins that also control dendritic development and may interact with dFMR1. Molecular mechanisms underlying many biological processes are highly conserved throughout evolution. Studies of the mechanisms that control dendritic development in Drosophila may help us understand similar processes in human brains. The insights gained from these studies may also contribute to our understanding of fragile X syndrome. ? ?
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