IFT, Intraflagellar Transport, discovered in Chlamydomonas in our laboratory, is essential for the assembly and maintenance of almost all eukaryotic cilia and flagella. Studies of the genes involved in IFT and its mechanism have led to new findings on the role of cilia/flagella (interchangeable terms) in many pathologies where the role of cilia was heretofore unsuspected. Because ciliary signaling processes, and their receptors on the ciliary membrane, are key to many of these pathologies, the proposed research is directed at determining how channels/receptors are targeted to the flagellar membrane, and to the flagellar axoneme through a proposed flagellar pore structure, and how IFT is involved in this transit process. We will determine, for the first time, the high resolution ultrastructure of the IFT particles both in situ and as isolated particles with Cryo-EM. Because there is mounting evidence, from our laboratory and others, that the cilium is involved in the control of the cell cycle, one of our most important goals is to determine the molecular interactions between one of the IFT polypeptides, a small G protein, and the cell cycle. Finally, one of our initial aims, 40 years ago, in establishing systems of cilia and flagellar regeneration, was to study how the cell recognizes the lack of its flagella and up-regulates hundreds of genes rapidly after flagellar detachment;we will determine what cytoplasmic factors are responsible for this transcriptional up-regulation.

Public Health Relevance

This proposal extends our study of intraflagellar transport (IFT) and how this motility process participates in the assembly and maintenance of eukaryotic cilia/flagella. Studies on the genes and mechanisms underlying IFT have led to new insight into the role of cilia in many pathologies where this role was heretofore unsuspected. Among these are situs inversus, retinal degeneration, developmental diseases of bone, muscle and connective tissue, cystic diseases of the kidney, liver and pancreas, as well as syndromes that include obesity and diabetes. The proposed research is directed at basic cell and molecular aspects of IFT which have not yet been well-researched.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Structure and Function (CSF)
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Gindhart, Joseph G
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Wood, Christopher R; Rosenbaum, Joel L (2014) Proteins of the ciliary axoneme are found on cytoplasmic membrane vesicles during growth of cilia. Curr Biol 24:1114-20
Satish Tammana, Trinadh V; Tammana, Damayanti; Diener, Dennis R et al. (2013) Centrosomal protein CEP104 (Chlamydomonas FAP256) moves to the ciliary tip during ciliary assembly. J Cell Sci 126:5018-29
Yuan, Shiaulou; Zhao, Lu; Sun, Zhaoxia (2013) Dissecting the functional interplay between the TOR pathway and the cilium in zebrafish. Methods Enzymol 525:159-89
Wood, Christopher R; Huang, Kaiyao; Diener, Dennis R et al. (2013) The cilium secretes bioactive ectosomes. Curr Biol 23:906-11
Mencarelli, Caterina; Mitchell, Aaron; Leoncini, Roberto et al. (2013) Isolation of intraflagellar transport trains. Cytoskeleton (Hoboken) 70:439-52
Wood, Christopher R; Wang, Zhaohui; Diener, Dennis et al. (2012) IFT proteins accumulate during cell division and localize to the cleavage furrow in Chlamydomonas. PLoS One 7:e30729
Kohno, Takahiro; Wakabayashi, Ken-ichi; Diener, Dennis R et al. (2011) Subunit interactions within the Chlamydomonas flagellar spokehead. Cytoskeleton (Hoboken) 68:237-46
Diener, Dennis R; Yang, Pinfen; Geimer, Stefan et al. (2011) Sequential assembly of flagellar radial spokes. Cytoskeleton (Hoboken) 68:389-400
Ferrante, Paola; Diener, Dennis R; Rosenbaum, Joel L et al. (2011) Nickel and low COýýý-controlled motility in Chlamydomonas through complementation of a paralyzed flagella mutant with chemically regulated promoters. BMC Plant Biol 11:22
Parker, Jeremy D K; Hilton, Laura K; Diener, Dennis R et al. (2010) Centrioles are freed from cilia by severing prior to mitosis. Cytoskeleton (Hoboken) 67:425-30

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