The overall goal of this research is to increase our understanding of how cilia beat by dissecting the molecular mechanisms and regulation of ciliary motility on a molecular level. Cilia and flagella are conserved and ubiquitous microtubule-based organelles with important roles in cell locomotion, fluid transport, sensation, cell signaling and development, which are critical processes for the survival and proper function of many eukaryotic cells and tissues. In humans, defects in the motility and assembly of cilia are responsible for numerous congenital diseases, such as primary ciliary dyskinesia, chronic respiratory disease, impaired fertility, brain developmental defects, congenital heart disease and randomization of the left-right body axis. Cilia motility is driven by the coordinated activities of thousands of dynein molecules, comprised of multiple isoforms. Our previous studies of wild type and mutant cilia, and actively beating cilia have opened a new window into the functional organization of motile cilia. However, long-standing fundamental questions remain about how regulatory signals change dynein?s activity on a molecular level, what are the roles of the different regulatory complexes during ciliary motility, and how dyneins are spatially and temporally coordinated to generate the oscillatory beating typical for cilia. Building on a strong premise of both published and preliminary new data, this proposal directly addresses these critical gaps through three specific aims that are directed at (Aim 1) revealing mechanisms by which dynein?s action is regulated to initiate and propagate ciliary waves, (Aim 2) determine the patterns of dynein activity that generate different ciliary waveforms, and (Aim 3) characterizing ciliary components that assemble only on specific doublets to ask if their inherently asymmetric distribution contributes to producing ciliary beating. We use a powerful and innovative combination of modern approaches that include cryo-electron tomography to image mutant cilia and tagged proteins with molecular resolution, genetics and proteomics, an alternate model organism to study cilia, and a state-of-the-art ?cutting? technique to look ?deeper inside? cells than previously possible. We expect that our combined studies will provide important new conceptual and mechanistic insights into ciliary motility and regulation, which will also impact our understanding of ciliary diseases.

Public Health Relevance

The proper function of several vital organs in humans requires the activity of cilia, and defects in ciliary assembly and motility are responsible for a wide variety of life-threatening, genetic disorders, such as chronic respiratory disease, congenital heart disease, brain developmental defects, and primary ciliary dyskinesia. Using innovative methods, our work addresses fundamental questions about how the motor protein dynein works and how thousands of these motors are coordinated to give rise to normal movement of a cilium. We expect that this research will provide new insights into the underlying mechanisms of ciliary-linked disorders in humans, which is a prerequisite to the development of therapeutic interventions.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Ainsztein, Alexandra M
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University of Texas Sw Medical Center Dallas
Anatomy/Cell Biology
Schools of Medicine
United States
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Fu, Gang; Wang, Qian; Phan, Nhan et al. (2018) The I1 dynein-associated tether and tether head complex is a conserved regulator of ciliary motility. Mol Biol Cell 29:1048-1059
Lin, Jianfeng; Nicastro, Daniela (2018) Asymmetric distribution and spatial switching of dynein activity generates ciliary motility. Science 360:
Hunter, Emily L; Lechtreck, Karl; Fu, Gang et al. (2018) The IDA3 adapter, required for intraflagellar transport of I1 dynein, is regulated by ciliary length. Mol Biol Cell 29:886-896
Urbanska, Paulina; Joachimiak, Ewa; Bazan, Rafa? et al. (2018) Ciliary proteins Fap43 and Fap44 interact with each other and are essential for proper cilia and flagella beating. Cell Mol Life Sci 75:4479-4493
Bower, Raqual; Tritschler, Douglas; Mills, Kristyn VanderWaal et al. (2018) DRC2/CCDC65 is a central hub for assembly of the nexin-dynein regulatory complex and other regulators of ciliary and flagellar motility. Mol Biol Cell 29:137-153
Nechipurenko, Inna V; Berciu, Cristina; Sengupta, Piali et al. (2017) Centriolar remodeling underlies basal body maturation during ciliogenesis in Caenorhabditis elegans. Elife 6:
Alford, Lea M; Stoddard, Daniel; Li, Jennifer H et al. (2016) The nexin link and B-tubule glutamylation maintain the alignment of outer doublets in the ciliary axoneme. Cytoskeleton (Hoboken) 73:331-40
Song, Kangkang; Awata, Junya; Tritschler, Douglas et al. (2015) In situ localization of N and C termini of subunits of the flagellar nexin-dynein regulatory complex (N-DRC) using SNAP tag and cryo-electron tomography. J Biol Chem 290:5341-53
Vasudevan, Krishna Kumar; Song, Kangkang; Alford, Lea M et al. (2015) FAP206 is a microtubule-docking adapter for ciliary radial spoke 2 and dynein c. Mol Biol Cell 26:696-710
Urbanska, Paulina; Song, Kangkang; Joachimiak, Ewa et al. (2015) The CSC proteins FAP61 and FAP251 build the basal substructures of radial spoke 3 in cilia. Mol Biol Cell 26:1463-75

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