The perennial organelle: assembly and disassembly of the primary cilium

Abstract

Primary cilia contain signaling receptors of diverse classes, and ciliary dysfunction results in a variety of developmental defects. Thus, primary cilia are thought to have an important role in sensing and transducing cellular signals. Although there is clear evidence demonstrating that these organelles are assembled and disassembled dynamically as cells progress through the cell cycle, the mechanisms by which the cell cycle controls the assembly and disassembly of the primary cilium remain poorly understood. In this Commentary, we review the basic cellular mechanisms that underlie the early stages of cilium assembly and discuss how the cell cycle communicates with the ciliation program. A commonly held view is that ciliation occurs exclusively in cells that have exited the cell cycle and entered quiescence or differentiation. However, this concept is at odds with the finding that, during development, many actively proliferating cells require cilia-mediated signaling pathways to instruct their developmental fate. Here, we reassess the quiescence-centric view of ciliation by reviewing historic and current literature. We discuss ample evidence that cilia are in fact present on many proliferating cells, and that a transient peak of ciliation before the G1-S transition might be tightly coupled to entry into the DNA replication phase. Finally, we touch on the relationship between the ciliation and cell-division cycles and the tissue distribution of primary cilia in order to highlight potential roles for the primary cilium in restraining cells from the hyperproliferative state that contributes to cancer.

Fig. 1.

Major structural features and functions of primary cilia, basal bodies and centrioles. The primary cilium is comprised of a basal body, an axoneme and the ciliary membrane. Basal bodies are mother centrioles that have been modified by the addition of defining accessory structures including transition fibers, basal feet and caps, and striated rootlets. The triplet microtubules of the basal body centriole give rise to the doublet microtubules of the ciliary axoneme at the region of the transition zone. Centrioles are typically found as orthogonal pairs comprising a mother and a daugher, the former being associated with specialized functions.

Fig. 2.

Molecular control of the ciliation cycle. A growing number of proteins are now recognized to regulate primary cilium assembly at the centriole. CP110 caps the distal ends of the mother centriole. The release of CP110 and CEP97 from the mother centriole, coupled to the activities of CDKs, permits microtubule elongation and axoneme elongation. CPAP promotes centriole elongation. However, the relationship between CPAP and axoneme assembly remains uncharacterized. Cilium disassembly as cells re-enter the cell cycle can be mediated by HEF1- and Aurora-A-mediated activation of HDAC6, which in turn, might promote cilium disassembly by deacetylating axonemal microtubules.

Fig. 3.

Relationship between cilium disassembly and DNA synthesis. Isolated serum components exhibit separable effects on ciliation and the DNA replication machinery. Biphasic primary cilium disassembly occurs as cells enter the cell cycle and begin to synthesize DNA following treatment with serum, which contains both platelet-poor plasma and PDGF. The second round of cilium disassembly occurs coincident with initiation of DNA replication. PDGF induces one round of cilium disassembly but reassembly and DNA synthesis do not take place. By contrast, platelet-free plasma is capable of inducing neither cilium disassembly nor DNA synthesis. PFP, platelet-free plasma. Reproduced from Tucker and Pardee (Tucker and Pardee, 1979) with permission.

Fig. 4.

Inverse relationship between stable plasma-membrane associations and ciliation. The epithelia of ducts and tubules, as found in the nephron, the pancreatic ducts and the hepatobiliary tree, exhibit substantial portions of lumen-exposed plasma membrane. By contrast, cells in which the plasma membranes are mostly apposed to those of neighboring cells or to basement membranes (e.g. pancreatic acini or liver hepatocytes) tend not to ciliate.