Control of centriole number in multiciliated cells

Specialized multiciliated cells (MCCs) elaborate dense motile cilia that beat in a coordinated manner to drive fluid flow over epithelial surfaces. Defects in motile cilia formation or beating lead to fluid buildup in the brain, increased respiratory tract infections, and infertility. Centrioles reside at the base of each cilium and serve as a template for cilium assembly. In cycling cells, centriole formation is tightly controlled so that a single new procentriole forms adjacent to each of the two parent centrioles. However, MCCs deviate from this strict numerical control to produce hundreds of centrioles to serve as the foundation for building hundreds of motile cilia. Most of the centrioles amplified by MCCs develop on the surface of cell-type-specific organelles called deuterosomes, while a smaller number grow through the centriolar pathway in association with the two parent centrioles. The deuterosome organelle is thought to have evolved to control the massive production of centrioles. We have interrogated the function of the deuterosome using a knockout mouse model. Surprisingly, our findings revealed that, in contrast to the current dogma, deuterosomes are dispensable for centriole amplification and multiciliogenesis. Moreover, MCCs lacking both parent centrioles and deuterosomes amplify the appropriate number of centrioles inside a cloud of pericentriolar material. This challenges the current thinking for how centriole amplification is controlled by showing that centriole number is set independently of their growing platforms in MCCs. We conclude that massive centriole production in MCCs is a robust process that relies on centriole self-assembly. While uncommon in mammals, this so-called de novo generation of centrioles has been observed in species such as the flatworm Planaria. We are now investigating how the centriole biogenesis machinery is tuned to control centriole assembly in MCCs. 

 

Selected papers

Cell cycle proteins moonlight in multiciliogenesis.

Levine, M.S., and Holland, A.J. Science. 2017. 358(6364): 716-8.

 

Massive centriole production can occur in the absence of deuterosomes in multiciliated cells.

Mercey, O.*, Levine, M.S.*, LoMastro, G., Rostaing, P., Brotslaw, E., Gomez, V., Kumar, A., Spassky, N., Mitchell, B.J., Meunier, A.* and Holland, A.J.* Nature Cell Biology. 201921: 1544-52. *equal contribution.