Supernumerary Centrosomes Nucleate Extra Cilia and Compromise Primary Cilium Signaling

Abstract

Summary The primary cilium is a nexus of cell signaling, and ciliary dysfunction is associated with polycystic kidney disease, retinal degeneration, polydactyly, neural tube defects, and obesity (ciliopathies) [1]. Signaling molecules for cilium-associated pathways are concentrated in the cilium, and this is essential for efficient signaling. Cilia are nucleated from centrioles, and aberrant centriole numbers are seen in many cancers and in some ciliopathies [2]. We tested the effect of supernumerary centrioles on cilium function, and found that cells with extra centrioles often formed more than one cilium, had reduced ciliary concentration of Smoothened in response to Sonic hedgehog stimulation, and reduced Shh pathway transcriptional activation. This ciliary dilution phenotype was also observed with the serotonin receptor Htr6, fibrocystin PKHD1, and Arl13b. The presence of extra centrioles and cilia disrupted epithelial organization in 3-D spheroid culture. Cells mutant for the tuberous sclerosis gene Tsc2 also had extra cilia and diluted ciliary protein. In most cells extra cilia were clustered and shared the same ciliary pocket, suggesting that the ciliary pocket is the rate-limiting structure for trafficking of ciliary proteins. Thus, extra centrioles and cilia disrupt signaling, and may contribute to disease phenotypes.

C-NAP1 and rootletin restrain DNA damage-induced centriole splitting and facilitate ciliogenesis

“…We occasionally observed multiple cilia after irradiation, often emerging side by side, possibly from a single ciliary pocket, as has been observed recently, where multiple cilia were formed after Plk4 overexpression induced supernumerary centrioles. 42 These multiple cilia only ever grew from mature centrioles, as confirmed by cenexin staining (Fig. 3B).…”

How do cilia organize signalling cascades?

“…Increasing chemical activities by concentrating molecules in cilia constitutes an attractive hypothesis for how cilia could participate in signalling. Indeed, Mahjoub & Stearns [11] found that diluting Hedgehog signalling intermediates into multiple primary cilia decreased pathway activation. An alternative model views cilia as the assembly point for specific scaffolds that bring together entire signalling modules in close proximity.…”

Epidermal development, growth control, and homeostasis in the face of centrosome amplification

“…Numerical aberrations in centrosome numbers have been demonstrated to alter ciliary signaling and have been proposed to be the underlying cause for certain defects in tissue organization (7,8). In addition, recent genetic studies on the master regulator of centrosome number, polo-like kinase 4 (PLK4), have shown that, whether too few or too many, perturbations in centrosome numbers can directly impede brain development, leading to microcephaly both in mice and in humans (9,10).…”