The importance of a single primary cilium

Abstract

The centrosome is the main microtubule-organizing center in animal cells, and helps to influence the morphology of the microtubule cytoskeleton in interphase and mitosis. The centrosome also templates the assembly of the primary cilium, and together they serve as a nexus of cell signaling that provide cells with diverse organization, motility, and sensory functions. The majority of cells in the human body contain a solitary centrosome and cilium, and cells have evolved regulatory mechanisms to precisely control the numbers of these essential organelles. Defects in the structure and function of cilia lead to a variety of complex disease phenotypes termed ciliopathies, while dysregulation of centrosome number has long been proposed to induce genome instability and tumor formation. Here, we review recent findings that link centrosome amplification to changes in cilium number and signaling capacity, and discuss how supernumerary centrosomes may be an important aspect of a set of cilia-related disease phenotypes.

Keywords: cancer; centriole; centrosome; ciliopathy; cilium.

Figure 1. Anatomy of the centrosome-cilium complex. At the core of the centrosome are a pair of centrioles, barrel-shaped structures composed of nine triplet-microtubules. Each centrosome contains a mother and daughter centriole arranged in an orthogonal configuration, which are surrounded by a matrix of proteins called the pericentriolar material (PCM). At the distal end of the older mother centriole are the centriolar appendages, which play important roles in anchoring microtubules as well as tethering the mother centriole to the membrane to induce ciliogenesis. The axoneme of the primary cilium is composed of nine doublet microtubules that grow from the microtubules of the mother centriole, and is surrounded by a ciliary membrane that is distinct from the rest of the plasma membrane.

Figure 2. Supernumerary centrosomes nucleate extra cilia and compromise ciliary signaling. (A) Examples of fibroblast cells with amplified centrioles and cilia. Centriole amplification was achieved by briefly expressing Plk4. Cells assembled excess centrioles in S-phase, which clustered together at the poles of the mitotic spindle. Once cells completed mitosis and entered a quiescent stage, the majority of cells possessed more than one primary cilium. Cells were stained for glutamylated tubulin (centrioles and cilia; red) and DNA (blue). Images were reproduced with permission from reference 54. (B) Model depicting ciliary dysfunction caused by dilution of ciliary signaling component (red) in super-ciliated cells. In normal mono-ciliated cells, ciliary proteins are concentrated within the ciliary compartment, and this is critical for pathway activation. In super-ciliated cells, the ciliary protein is distributed among multiple cilia, resulting in a reduced concentration of the signaling component per unit length cilium, causing defective pathway activation.

Figure 3. Mechanisms by which centrosome amplification may contribute to cell transformation. (A) Supernumerary centrosomes can lead to an increase in the frequency of lagging chromosomes, inducing aneuploidy through chromosome mis-segregation. (B) Centrosome amplification can modulate the number of primary cilia per cell, resulting in compromised ciliary signaling.