William Dentler

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.