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Centriole assembly and function

 

Principal Investigator: Alexander Dammermann

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 distinct 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 importance 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 to investigate the fundamental and conserved molecular mechanisms underlying centriole assembly and function. In previous work we have taken advantage of the availability of data from genome-wide RNAi-based screens 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 core centriolar 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, in particular what are the specific mechanistic contributions of each of the six proteins in the centriole assembly pathway; 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.

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