Building it up and taking it down: the regulation of vertebrate ciliogenesis

Abstract

Primary cilia project from the surface of most vertebrate cells, and function in sensation and signaling during both development and adult tissue homeostasis. Mounting evidence links ciliary defects with a wide variety of diseases, underscoring the importance of understanding how these dynamic organelles are assembled and maintained. However, despite their physiological and clinical relevance, the logic and machinery that regulate ciliogenesis remain largely enigmatic. Here, we summarize emerging data that connect the assembly and disassembly of the primary cilium to cell cycle progression and we examine how determinants of cell architecture, including the planar cell polarity pathway, may regulate ciliogenesis. Additionally, identification of the genes underlying diverse ciliopathies in human patients is shedding light on the regulation of the formation of this complex organelle.

Figure 1. Dual use of the centrioles during cell cycle and primary cilium formation

In most cells, primary cilium formation first occurs during G1 following centrosomal docking to the membrane. IFT and accessory proteins build the ciliary axoneme, which extends directly from the mother centriole’s triplet microtubules. During this stage of the cell cycle, as well as in G0, the cilium functions as a cellular antenna, interpreting extracellular signals such as Hedgehog and PDGF. Upon entry into S phase, the cell’s centrioles and the DNA begin to replicate. The centrioles reach maturity during late G2, at which point the cilium is disassembled so that the engaged centrioles can be liberated for mitotic spindle formation. Once cell division is complete, the centrioles can proceed to ciliary re-assembly in G1.

Figure 2. A model of CP110 and AuroraA-mediated coordination of ciliogenesis with the cell cycle

CP110 is recruited to the centrosome by Cep97, where it inhibits ciliogenesis (a). Activation of CDK2 leads to CP110 phosphorylation, allowing ciliogenesis to occur (b). Two other proteins, HEF1 and AuroraA (AurA) localize to the ciliary basal body and participate in ciliary deassembly prior to mitosis (c). Upon growth factor (GF) stimulation, HEF1 activates AuroraA (d), which subsequently phosphorylates HDAC6 (e). Activated HDAC6 promotes ciliary disassembly by de-acetylating axonemal tubulin (f).

Figure 3. Possible mechanisms by which VHL promotes ciliogenesis

1) VHL serves as an E3 ubiquitin ligase that targets HIF for destruction. HIF may inhibit ciliogenesis itself. 2) VHL binds and promotes the oriented growth of microtubules. As microtubules form the core of the ciliary axoneme, VHL-mediated stabilization of these microtubules may be necessary for ciliary maintenance. 3) VHL binds to the Par3-Par6-aPKC complex, which is necessary for apicobasal polarization. This polarization may be necessary for correct docking of the mother centriole to the apical plasma membrane, an early step in ciliogenesis. 4) VHL may ubiquitinate cilium-associated aPKC, inhibiting the ability of aPKC to dissociate microtubules from the basal body.