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PEARSON LAB DESCRIPTION

Centriole Biogenesis and Stabilization for Centrosomes and Cilia

In the Pearson Lab, we delve into several fascinating aspects of centrioles and basal bodies as they perform roles in organizing centrosomes and cilia. Centrosomes consist of a pair of centrioles surrounded by a matrix of pericentriolar material that nucleates cytoplasmic microtubules. During G0/G1 of the cell cycle, centrioles are commonly modified to serve as basal bodies that organize cilia. These cilia (known as primary cilia), sense their environment and transmit signals to the cell nucleus. Other cells produce motile cilia that produce hydrodynamic force generating fluid flow. In the case of motile cilia and the basal bodies that organize them, we capitalize on the ciliated protist, Tetrahymena thermophila, to understand how centrioles and basal bodies assemble, organize at the cell surface and resist mechanical stress produced by ciliary beating.

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TOULOUSE TALK

Altered centrosomal trafficking disrupts cilia assembly and signal transduction in Down syndrome

Domenico F. Galati, Andrew Pham, Kelly D. Sullivan, Joaquin Espinosa and Chad G. Pearson

Ciliopathies share substantial phenotypic overlap with Down syndrome (DS; trisomy 21), including the presence of congenital heart defects, craniofacial abnormalities and altered cerebellar development. Whether these similarities result from cilia defects in DS cells is not known. To begin to address this possibility, we investigated cilia formation and ciliary signaling in DS cells. Trisomy 21 increases the expression of the chromosome 21 gene Pericentrin. At normal expression levels, Pericentrin localizes ciliary assembly and signaling proteins to the centrosome via a trafficking network that traverses cytoplasmic microtubules. In DS, excess Pericentrin disrupts the spatial organization of the ciliary trafficking network. This is because excess Pericentrin increases gamma-tubulin levels at the centrosome, which causes increased and disorganized cytoplasmic microtubules. In turn, the altered microtubule network disrupts dynamic Pericentrin trafficking events to and from the centrosome. Pericentrin is required to localize the cilia assembly factor, IFT20, to the centrosome for eventual loading into the ciliary compartment. In DS, Pericentrin trafficking defects reduce the centrosomal level of IFT20, which, ultimately, decreases cilia formation. When cilia do form in the presence of excess Pericentrin, they do not properly transduce Sonic hedgehog (Shh). These results demonstrate that increased gene dosage of ciliary trafficking proteins disrupts the dynamic recruitment of ciliary assembly and signaling proteins. We propose that altered ciliary trafficking is a potential disease mechanism that may contribute to ciliopathy-like phenotypes in Down syndrome and other aneuploid disorders.