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Mechanisms of Assembly of Motile Cilia and Flagella


Cilia and flagella are evolutionarily ancient organelles that perform motility and/or sensory functions in most protozoans and metazoans. They are microtubule-based projections on the cell surface anchored by modified centrioles at the base. In vertebrates, cilia play important developmental roles such as the establishment of left-right asymmetry, tissue homeostasis and cell differentiation. In particular, the vertebrate Hedgehog (Hh) signaling pathway depends on the immotile primary cilium for the trafficking of signal receptors and effectors. The putative serine-threonine kinase Fused (Fu) is an indispensable regulator of the Drosophila Hh signaling system. However, the mammalian ortholog does not participate in the Hh pathway and instead assists in the construction of motile cilia with the "9+2" arrangement of microtubules in the axoneme. Therefore, the functions of Fu have diverged between Hh signaling and motile ciliogenesis. In this dissertation, we show that mouse Fu and its interacting protein Kif27 are ciliary proteins that function in the construction of the central pair microtubules of motile cilia in the mouse trachea and the oviduct. We show that Fu physically associates with proteins in the central pair doublet and plays an important role in the establishment of directional fluid flow in the lumen of the mouse oviduct. Finally, we investigate the role of Fu in the construction of the sperm flagellum with the use of transgenic mouse models. Surprisingly, Fu does not appear to be needed for the construction of the central pair apparatus of the sperm flagellum. Instead, we demonstrate that it is required for the integrity and proper spatial distribution of the components of the fibrous sheath. We also discover that Fu is involved in the development of the sperm head structure through its interaction with the microtubule-based manchette transport system. The data in this dissertation suggest that Fu is an adaptable protein that has been co-opted for multiple functions involving trafficking on the microtubules across diverse phyla. Our results provide useful insights into the regulation and conservation of motile cilia and flagella assembly.

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