Microtubules have specialized configurations within different regions of the neuron. Local changes in the configuration and behavior of microtubules underlie important events in neuronal differentiation such as elongation, retraction, navigation, branching, and sprouting of axons and dendrites. Assembly dynamics and interactions with structural proteins have been studied extensively as mechanisms for configuring these microtubule arrays. Recent studies indicate that neuronal microtubules are also configured by forces generated by molecular motor proteins. A model has emerged suggesting that cytoplasmic dynein drives microtubules down axons and dendrites, while the kinesin-related motor protein termed CHO1/MKLP1 drives microtubules down dendrites but not axons. Another kinesin-related motor capable of configuring microtubules termed Eg5 is enriched in regions of new growth. These motors are all crucial for organizing microtubules in the mitotic spindle of dividing cells, suggesting that neuronal and mitotic microtubules may be organized by similar principles and molecules. It is reasonable to speculate that, as is the case with the mitotic spindle, neurons may utilize a host of complementary and antagonistic motor-driven forces to drive microtubules retrogradely as well as anterogradely, to zipper microtubules into bundles, to splay apart bundles, and to integrate microtubules with other cytoskeletal elements. Available data suggest that cytoplasmic dynein and CHO1/MKLP1 are the main workhorses for transporting microtubules in neurons, but that forces generated by other so-called mitotic motors such as Eg5 and KIF15 are essential for modulating many of the intricate microtubule behaviors necessary for neuronal morphogenesis. It is unclear whether neurons use precisely the same forms of the motors utilized in mitosis or variants with somewhat different properties. This application proposes to investigate these issues using a battery of approaches, including high-resolution imaging of microtubule behaviors in living neurons. Studies will be performed to ascertain the precise isoforms of these motors expressed in neurons, and to test specific hypotheses regarding their functional roles. These studies will provide information important for understanding neuronal development, plasticity of the nervous system, neuropathies involving the cytoskeleton, and regeneration following injury.
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