Centrosomes contribute to mitotic spindle organization and orientation in mitosis, and to the assembly of primary cilia in nondividing cells. Centrosome anomalies affect the fidelity of spindle and cilia function and are associated with ciliopathies, microcephaly, dwarfism, cancer and other human disorders. Cilia proteins are found at centrosomes in mitotic cells (spindle poles) and some are involved in the orientation of cell division. However, the function of these cilia proteins in mitotic cells is not known. Preliminary results from the Doxsey laboratory suggest that cilia proteins required for transporting material up and down cilia in noncycling cells (intraflagellar transport, IFT) also transport material to and from spindle poles in mitotic cells. Disruption of these cilia proteins induces defects in mitotic spindle orientation, astral microtubule organization, spindle pole function and mitotic progression. Other cilia proteins localize to additional mitotic structures such as kinetochores and midbodies, suggesting additional mitotic functions of this class of proteins. The overall goal of this proposal is to test the hypothesis that IFT complexes involved in cilia formation and function in noncycling cells, are re-directed, at least in part, to perform previously unanticipated mitotic functions. To test this, we will address the molecular mechanism of IFT protein complex function in mitotic spindles. Our preliminary studies indicate that IFT88 forms particles in cells that transport microtubule-nucleating proteins to spindle poles using the dynein motor.
The specific aims are designed to test if IFT protein complexes serve as carriers of mitotic cargoes and if dynein provides the force for their movement. Novel aspects of the work include the identification of a novel mechanism for spindle pole assembly and spindle orientation, the use of super- resolution microscopy to image the dynamics of novel IFT protein-containing particles in living mitotic cells, the characterization of new mitotic IFT protein-dynein complexes using new affinity systems and the use of in vitro assays to study dynein-based motility. This work has the potential to identify a new molecular pathway for spindle pole assembly and to define novel functions of cilia proteins in mitotic cells.
We seek to uncover a novel molecular pathway for spindle organization, which is relevant to a number of human disorders including cancer, developmental abnormalities, ciliopathies, microcephalies and primordial dwarfisms. A long-term goal of this work is to develop new therapeutic strategies for prevention or treatment of disorders arising from spindle dysfunction.
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