Centriole Biogenesis for Centrosomes and Cilia
Microtubules are responsible for diverse cellular functions, ranging from trafficking and force generation to structural platforms for cellular sensation. Variations in microtubule function are achieved because their fascinating structures and dynamics can be modulated by different microtubule organizing centers (MTOC) and regulatory events. Integral to microtubule organization is the centriole, the core structure around which vertebrate centrosomes and cilia are assembled. Increasingly appreciated in human disease, defects in centrioles, centrosomes, and cilia contribute to both human cancer and ciliary diseases, or ciliopathies, that exhibit an array of pathologies including polydactyly, situs inversus, kidney cysts, blindness, respiratory illness, and mental retardation. This diversity in pathologies is a result of the many specialized cellular processes in which centrioles and cilia function to generate forces or to sense the surrounding environment.
Our lab is focused on the structural and molecular events for centriole biogenesis. Electron microscopy studies performed a half a century ago defined the morphological events leading to a mature centriole. However, the hundreds of molecules that comprise these structures were unknown. Now with a large inventory of centriole components from proteomic studies, we can explore how these proteins collaborate to assemble the nine-fold radially symmetric centriole structure. To do so, the lab is focused on several projects:
Determine the centriole cartwheel proteome.
Identify the functional complexes of the centriole.
Determine the localization domains and dynamics of centriole proteins.
Determine how centrioles mature and stabilize to resist to mechanical forces.
We use multiple model systems in conjunction with electron and high-resolution, quantitative fluorescence microscopy. We have developed Tetrahymena thermophila for molecular studies of centriole assembly and function. This ciliated protist, with its 750 centrioles per cell, is a fantastic system to study the assembly process. Tetrahymena has the unique advantage of genetic manipulability combined with hundreds of centriole assembly events per cell cycle. Results found for Tetrahymena are often expanded upon in our studies of human centrioles.