The goal of this project is to understand the mechanism by which calcium alters the size and shape of ciliary and flagellar bends to control motility. In mammals, motile cilia / flagella are required for sperm propulsion, removal of debris from the respiratory tract, circulation of cerebrospinal fluid, and even for determination of the left-right body plan during development. As a consequence, defects in motility may result in impaired fertility, respiratory distress, hydrocephalus, and/or randomization of the left-right body axis. The architecture and molecules which comprise these organelles are remarkably conserved. Therefore, fundamental principles for motility obtained from studies of any single cell type are generally applicable to all eukaryotic cilia and flagella. Understanding how dynein is regulated to produce the complex waveforms typical of beating cilia / flagella is still the most pressing unanswered question in the field of ciliary motility. Substantial data has contributed to a model in which the axonemal microtubules act as a scaffold for the assembly of molecules that form a signal transduction pathway that ultimately regulates dynein. The second messenger calcium impacts upon these signal transduction pathways to alter beating in response to extracellular cues. The discovery that calmodulin (CaM) is a key calcium sensor and that highly conserved CaM-binding proteins are localized to axonemal structures known to play a role in motility form the foundation for this work. The proposed experiments are designed to test the hypothesis that specific CaM-binding proteins are part of a signal transduction network that alters motility in response to calcium.
The Specific Aims of this proposal are to 1) develop strains with defects in CaM interactors;2) test the hypothesis that central apparatus associated CaM plays a role in modulating dynein activity on specific doublet microtubules;and 3) test the hypothesis that a spoke-associated CaM binding complex, the CSC, is both a structural and functional component of a signal transduction pathway that modulates dynein activity. These studies have the potential to define a molecular mechanism for CaM mediated signal transduction that includes specific protein-protein interactions acting as switches to control dynein activity, as well as the broader potential to define new principles for the targeting and anchoring of molecules that define signal transduction pathways that regulate the dynein family of motors.
We are interested in defining mechanisms for calcium regulation of ciliary and flagellar motility. In mammals, motile cilia / flagella are required for sperm propulsion, removal of debris from the respiratory tract, circulation of cerebrospinal fluid, and even for determination of the left-right body plan during development (reviewed in Satir and Christensen, 2006). As a consequence, defects in motility may result in impaired fertility, respiratory distress, hydrocephalus, and/or randomization of the left-right body axis (reviewed in Badano et al, 2006).
|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|
|Dymek, Erin E; Smith, Elizabeth F (2012) PF19 encodes the p60 catalytic subunit of katanin and is required for assembly of the flagellar central apparatus in Chlamydomonas. J Cell Sci 125:3357-66|
|Goduti, Daniel J; Smith, Elizabeth F (2012) Analyses of functional domains within the PF6 protein of the central apparatus reveal a role for PF6 sub-complex members in regulating flagellar beat frequency. Cytoskeleton (Hoboken) 69:179-94|
|Heuser, Thomas; Dymek, Erin E; Lin, Jianfeng et al. (2012) The CSC connects three major axonemal complexes involved in dynein regulation. Mol Biol Cell 23:3143-55|
|Brown, Jason M; Dipetrillo, Christen G; Smith, Elizabeth F et al. (2012) A FAP46 mutant provides new insights into the function and assembly of the C1d complex of the ciliary central apparatus. J Cell Sci 125:3904-13|
|Dymek, Erin E; Heuser, Thomas; Nicastro, Daniela et al. (2011) The CSC is required for complete radial spoke assembly and wild-type ciliary motility. Mol Biol Cell 22:2520-31|
|Smith, Elizabeth F; Rohatgi, Rajat (2011) Cilia 2010: the surprise organelle of the decade. Sci Signal 4:mr1|
|DiPetrillo, Christen G; Smith, Elizabeth F (2011) The Pcdp1 complex coordinates the activity of dynein isoforms to produce wild-type ciliary motility. Mol Biol Cell 22:4527-38|
|DiPetrillo, Christen G; Smith, Elizabeth F (2010) Pcdp1 is a central apparatus protein that binds Ca(2+)-calmodulin and regulates ciliary motility. J Cell Biol 189:601-12|
|Dymek, Erin E; Smith, Elizabeth F (2007) A conserved CaM- and radial spoke associated complex mediates regulation of flagellar dynein activity. J Cell Biol 179:515-26|
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