The vertebrate cilium is a sensory organelle critical for a broad array of homeostatic mechanisms and paracrine signals. Notably, ciliopathy phenotypes manifest as both developmental structural defects and failure of left-right axis determination in a host of clinical disorders, as well as progressive degenerative phenotypes, suggesting that ciliary proteins serve important functions in organogenesis, tissue maintenance, and, potentially, regeneration. The field faces numerous challenges for the future, which include three major questions.
First, what are the similarities and differences (both structural and functional) between primary cilia in different cell types? Given the association of major developmental process with ciliary dysfunction, it is perhaps paradoxical that ciliopathies do not manifest more severe clinical phenotypes. In addition to the usual suspicions of differential tolerance for damage and regenerative ability, it is likely that not all cilia partake in the same signaling processes. To that end, the progress made toward characterizing the complete ciliary proteome must now be refocused toward understanding the protein complement of cilia in particular tissues and cell types.
Second, it is equally important to differentiate between the ciliary and nonciliary roles of these proteins. There is a pervasive ciliocentric view in the current literature—that a protein localizes to basal bodies and cilia in cultured cells and tissues can no longer serve as definitive evidence that a protein’s function is exclusively at the cilium. Several ciliary proteins are now known to serve multiple cellular functions, and it is likely that pools of ciliary proteins will be found in other compartments under specific physiological conditions. Therefore, the burden of proof for a ciliary phenotype in any model system will require multiple independent lines of evidence, including studies of ciliation and deciliation.
Third, the association of the primary cilium with Hedgehog and Wnt signaling opens up several areas of investigation. Most pressing is to identify other pathways in which the primary cilium might play a role. Intriguingly, if basal body integrity is indeed required for proteasomal targeting of a subset of signaling proteins, including, but not limited to, β-catenin (Gerdes et al., 2007
), we might expect pathways that require proteasomal processing to be modulated by the cilium. It is unlikely to be coincidental that both Hedgehog (Gli processing) and Wnt signaling (β-catenin degradation) rely heavily on proteasomal processing, and that disruption of both the basal body and cilium result in impaired proteasomal processing of Gli2/3 (Caspary et al., 2007
; Delous et al., 2007
; Haycraft et al., 2005
; Huangfu and Anderson, 2005
; Karmous-Benailly et al., 2005
) and impaired degradation of Dvl and β-catenin (Gerdes et al., 2007
; Simons et al., 2005
Finally, the near-ubiquitous presence of ciliated structures in vertebrates potentially contains some important evolutionary lessons. In invertebrates, such as Drosophila, only sensory neurons and sperm are ciliated, whereas in vertebrates, nearly every tissue type has cells that are ciliated at some point in their life cycle. We suggest that the role of the cilium in paracrine signaling might have been the direct outcome of the widespread presence of cilia in vertebrates. Clearly, though conserved throughout evolution, signal transduction pathways have diverged from invertebrate to vertebrate organisms. In Drosophila, the Hedgehog and PCP signaling pathways are organized differently than they are in mice and humans. However, it is unclear which fraction of a specific signaling pathway is regulated by the primary cilium, though such regulation is likely to be time and tissue specific.