The long-term goals of this research are to understand the structure, assembly, and function of cilia and flagella, and their roles in human health. The studies are utilizing Chlamydomonas and mice as model organisms, and are focused on processes and proteins that are highly conserved among ciliated organisms. A combination of genetic, biochemical and cell biological approaches will be taken. One process under investigation is intraflagellar transport (IFT), which is necessary for the assembly and maintenance of almost all cilia and flagella. I FT involves the movement of particles to the tip of the flagellum and back. These particles contain at least 16 different subunits, but almost nothing is known about the functions of the individual subunits. Studies will characterize Chlamydomonas null mutants defective in two highly conserved IFT-particle proteins, IFT46 and IFT20, to test the hypotheses that IFT46 is involved in transport of the outer dynein arms into the flagellum, and that IFT20 is involved in delivery of membrane proteins to the flagellum. Another process being studied is the mechanism of ciliary and flagellar movement. One protein recently implicated in this process is hydin, a component of the central pair (CP) of microtubules in the Chlamydomonas flagellar axoneme. Hydin appears to have a role in the CP/radial spoke signaling pathway that controls dynein arm activity. Experiments will be carried out to identify the proteins with which hydin interacts in both the CP and the radial spokes. In the mouse and possibly in humans, Hydin defects cause hydrocephalus, which is the lethal accumulation of cerebrospinal fluid in the ventricles of the brain. Studies will use mice defective in Hydin to determine if Hydin also is a CP protein in mammals, and if it is important for ciliary motility in the brain and airway. In related studies, a global analysis of Chlamydomonas CP proteins will be carried out to fill a large gap in our knowldedge of this important structure, and to facilitate studies of hydin and of CP/radial spoke interaction. Another important disease protein being investigated is nephrocystin-4. Defects in Nephrocystin-4 cause cystic kidney disease and retinal degeneration in humans. It is believed to be a protein of the ciliary transition region, but nothing is known about its function. A Chlamydomonas mutant lacking nephrocystin-4 will be characterized to learn more about this protein's specific location and function in the transition region. Defects in the processes and proteins under investigation cause disease in humans and vertebrate model organisms. The research will provide new information on the role of cilia and flagella in cystic kidney disease, retinal degeneration, primary ciliary dyskinesia, male infertility, and hydrocephalus.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Cell Structure and Function (CSF)
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Gindhart, Joseph G
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University of Massachusetts Medical School Worcester
Anatomy/Cell Biology
Schools of Medicine
United States
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Kubo, Tomohiro; Hou, Yuqing; Cochran, Deborah A et al. (2018) A microtubule-dynein tethering complex regulates the axonemal inner dynein f (I1). Mol Biol Cell 29:1060-1074
Wingfield, Jenna L; Mengoni, Ilaria; Bomberger, Heather et al. (2017) IFT trains in different stages of assembly queue at the ciliary base for consecutive release into the cilium. Elife 6:
Hou, Yuqing; Witman, George B (2017) The N-terminus of IFT46 mediates intraflagellar transport of outer arm dynein and its cargo-adaptor ODA16. Mol Biol Cell 28:2420-2433
Brown, Jason M; Mosley, Matthew; Montes-Berrueta, Daniela et al. (2017) Characterization of a new oda3 allele, oda3-6, defective in assembly of the outer dynein arm-docking complex in Chlamydomonas reinhardtii. PLoS One 12:e0173842
Schmidts, Miriam; Hou, Yuqing; Cort├ęs, Claudio R et al. (2016) Corrigendum: TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport. Nat Commun 7:11270
Kubo, Tomohiro; Brown, Jason M; Bellve, Karl et al. (2016) Together, the IFT81 and IFT74 N-termini form the main module for intraflagellar transport of tubulin. J Cell Sci 129:2106-19
Kubo, Tomohiro; Hirono, Masafumi; Aikawa, Takumi et al. (2015) Reduced tubulin polyglutamylation suppresses flagellar shortness in Chlamydomonas. Mol Biol Cell 26:2810-22
Hou, Yuqing; Witman, George B (2015) Dynein and intraflagellar transport. Exp Cell Res 334:26-34
San Agustin, Jovenal T; Pazour, Gregory J; Witman, George B (2015) Intraflagellar transport is essential for mammalian spermiogenesis but is absent in mature sperm. Mol Biol Cell 26:4358-72
McKenzie, Casey W; Craige, Branch; Kroeger, Tiffany V et al. (2015) CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice. Mol Biol Cell 26:3140-9

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