Molecular mechanisms of centriolar triplet microtubule formation

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Project Summary/Abstract Centrioles are conserved cellular organelles that template cilia for mediating cell signaling and motility, and recruit pericentriolar material to nucleate microtubules as part of the centrosome. Centrioles are extremely stable structures that persist over multiple cell cycles, and centriole number is controlled to ensure that each daughter cell inherits exactly two centrioles from its mother. Defects in centrosome and cilium function have been linked to a wide range of diseases, including cancer, microcephaly, and a set of syndromes known as ciliopathies. Within a centrosome, the older centriole in the pair templates the cilium, and together they form the centriole-cilium complex. Key features of this complex are the compound microtubules, which are a unique arrangement of microtubules linked together: three linked microtubules form the centriolar triplets, and two form the ciliary doublets. These compound microtubules occur only in the centriole-cilium complex, and are required for the structural integrity of the centriole and for protein trafficking in the cilium. Though the morphology of compound microtubules has long been appreciated, little is known about the mechanisms by which these microtubules form specifically at the centriole-cilium complex. In my postdoctoral work, I found that two members of the tubulin superfamily, delta-tubulin and epsilon-tubulin, are required for the centriolar triplet microtubules. The means by which these proteins act are unknown. Here, I propose to determine the mechanisms of compound microtubule formation through an integrated set of aims. Spanning both the mentored and independent phases, these aims will allow me to test the relative contributions of microtubule protofilaments themselves, as well as other proteins including delta- tubulin and epsilon-tubulin, to compound microtubule formation and stability. With the help of an outstanding collaborator and mentor team, I will train in research techniques, as well as skills for my career development. Together, this will create a strong foundation for an independent research career in understanding the roles of microtubule structures in human development and health.