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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM014642-44
Application #
8033120
Study Section
Cell Structure and Function (CSF)
Program Officer
Gindhart, Joseph G
Project Start
1975-09-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
44
Fiscal Year
2011
Total Cost
$678,459
Indirect Cost
Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Long, Huan; Zhang, Fan; Xu, Nannan et al. (2016) Comparative Analysis of Ciliary Membranes and Ectosomes. Curr Biol 26:3327-3335
Diener, Dennis R; Lupetti, Pietro; Rosenbaum, Joel L (2015) Proteomic analysis of isolated ciliary transition zones reveals the presence of ESCRT proteins. Curr Biol 25:379-84
Wood, Christopher R; Rosenbaum, Joel L (2015) Ciliary ectosomes: transmissions from the cell's antenna. Trends Cell Biol 25:276-85
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
Mencarelli, Caterina; Mitchell, Aaron; Leoncini, Roberto et al. (2013) Isolation of intraflagellar transport trains. Cytoskeleton (Hoboken) 70:439-52
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
Gupta, Anjali; Diener, Dennis R; Sivadas, Priyanka et al. (2012) The versatile molecular complex component LC8 promotes several distinct steps of flagellar assembly. J Cell Biol 198:115-26
Yuan, Shiaulou; Li, Jade; Diener, Dennis R et al. (2012) Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation. Proc Natl Acad Sci U S A 109:2021-6

Showing the most recent 10 out of 36 publications