Centrioles are small cylindrical organelles whose distinguishing feature is an outer wall composed of a nine-fold symmetric array of stabilized microtubules. Centrioles perform two important functions in eukaryotic cells: 1) they recruit pericentriolar material to form centrosomes that organize the microtubule cytoskeleton and position the mitotic spindle, and 2) they template cilia, cellular projections that perform a variety of critical sensory and motile functions. Centrosome and cilia abnormalities have been linked to aneuploidy and tumorigenesis as well as developmental disorders including ciliopathies and microcephaly. Despite their significance to human physiology and pathology, centrioles have remained poorly understood at the molecular level, largely due to the technical challenges posed by the small size of this organelle.
In our lab we are using a combination of biochemical, cell biological and genetic approaches in the nematode C. elegans and the fruit fly Drosophila melanogaster to investigate the fundamental and conserved molecular mechanisms underlying centriole assembly and function. In previous work we have used the C. elegans early embryo to define the molecular requirements for centriole assembly. The six-protein molecular pathway we identified has since been found to be conserved from ciliates to vertebrates, and is thought to form the core of the centriole assembly machinery in all eukaryotes. We further identified the hydrolethalus syndrome protein HYLS-1 as a protein that is incorporated into centrioles during their assembly to confer on them the ability to initiate cilia. The single amino acid missense mutation associated with hydrolethalus syndrome impairs HYLS-1 function in ciliogenesis, identifying this disorder as a severe (perinatal lethal) ciliopathy.
Current research builds on this foundation, seeking to answer three main questions: 1) How do centrioles assemble, and what are the molecular mechanisms that underlie their remarkable stability; 2) how do centrioles recruit pericentriolar material to form centrosomes and what is the molecular nature of this material; and 3) how do centrioles form cilia, focusing on the events immediately downstream of HYLS-1.
Start Lab in 2010