Regulation of ciliary and flagellar assembly
We study mechanisms that regulate the assembly of cilia and eukaryotic flagella. These organelles are best known for their ability to move protozoan and sperm cells or transport mucus over ciliated epithelial tissues but they also are essential organelles for a variety of cell signal transduction processes essential for the development and maintenance of metazoans. Cilia display receptors for vision, odor detection, and fluid flow in a variety of tissues. The failure to assemble and maintain cilia leads to a variety of diseases, collectively called ciliopathies that include anosmia, retinitis pigmentosia, Bardet-Biedl syndrome, polycystic kidney disease, and defects in heart and brain development. Most ciliopathies are autosomal recessive disorders that affect between 1 in 80,000 to 1 in 160,000 newborns and adults and many of these are associated with the ciliary membrane that surrounds the supportive and motile apparatus formed by the microtubular axoneme.
Our studies are focused on mechanisms that regulate the assembly of the microtubules and the surrounding membrane. Our major project is to determine the functions of microtubule cap structures that link the tips of ciliary microtubules to the ciliary membrane. We have characterized the structure of these cap structures and currently are in the process of isolating the caps and generating cap mutants that will provide insight into their functions. We used biochemical and proteomic approaches to identify potential cap proteins in Tetrahymena and are in the process of tagging cap genes with GTP to identify proteins that are found at ciliary tips.
A second project involves the assembly of membranes around Chlamydomonas flagella. These flagella continually shed membrane from their tips, near the cap structures, and, if membrane is not replaced, flagella disassemble. This reveals a mechanism by which flagellar microtubule assembly depends on a supply of membrane and that the membrane is critically important to maintain the microtubular cytoskeleton. These studies may provide a new understanding of the coordination between the assembly of microtubules and membranes.
- Dentler WL. (2012) A role for the flagellar membrane in flagellar growth and maintenance. PLOS1 in press
- Gaertig J, Wloga D, Vasudevan K, Guha M, Dentler W (2013) Discovery and functional evaluation of ciliary proteins in Tetrahymena thermophila. Methods in Enzymology in press
- Dentler WL (2008) Microtubule-membrane interactions in Chlamydomonas flagella. The Chlamydomonas Sourcebook, 2nd edition. G.B. Witman, ed. Academic Press, NY, 283-301.
- Dentler WL, VanderWaal K, Porter ME. (2009) Recording and analyzing IFT in Chlamydomonas Flagella. Methods Cell Biology 93:145-155. PMID: 20409816
- Lu J, Dentler WL, Lundquist EA. 2008 FLI-1 Flightless-1 and LET-60 Ras control germ line morphogenesis in C. elegans. BMC Dev Biol. 2008 May 16;8:54.
- Dentler, W.L. 2005 Intraflagellar transport (IFT) during assembly and disassembly of Chlamydomonas flagella. J. Cell Biol.170(4):649–659. PMID: 16103230
- Tam, LW, Dentler, WL, Lefebvre, PA. 2003. Defective flagellar assembly and length regulation in LF3 null mutants in Chlamydomonas. J. Cell Biol. 163(3):597–607. PMID: 14610061
- Song L, and Dentler WL 2001 Flagellar protein turnover in Chlamydomonas. J. Biol Chem. 276:29754–29763. PMID: 11384985
- Porter, M., Bower, K, Knott, J, and Dentler,W. 1999. Cytoplasmic dynein heavy chain 1b is required for flagellar assembly in Chlamydomonas. Mol. Biol. Cell. Mar;10(3):693–712.
- Tuxhorn JA, Daise TM, and Dentler WL. 1998. Characterization of a Chlamydomonas mutant exhibiting light-dependent flagellar shortening. Cell Motil Cytoskeleton 40(2):133–146.
- Dentler, W.L., and G.B. Witman. 1995. Cilia and Flagella. Methods in Cell Biology, Academic Press.
- Wang,W., Himes RH, and Dentler. WL 1994. The interaction of a plus-end binding ciliary microtubule protein complex with microtubules is regulated by endogenous protein kinase and phosphatase activities. J. Biol. Chem. 269:21460–21466.
- Wang W., Suprenant KA, and Dentler, WL. 1993. Reversible association of a 97kD protein complex found at the tips of ciliary microtubules with in vitro assembled microtubules. J. Biol. Chem. 268:24796–24807.
- Dentler, WL., and Adams, C. 1992. Flagellar microtubule dynamics in Chlamydomonas : Cytochalasin D induces periods of microtubule shortening and elongation; Colchicine induces disassembly of the distal, but not proximal, half of the flagellum. J. Cell Biol. 117:1289–1298.
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