Cilium length regulation in Caenorhabditis elegans

Nearly all vertebrate cells possess a primary cilium, akin to a cellular antenna, that plays essential roles in various physiological and developmental processes. Cilium length is tightly regulated to provide the optimal functions for each type of cell and tissue, such as the eye and kidney. Impairment of this regulation can result in cilium-associated disorders, collectively termed ciliopathies. The intraflagellar transport (IFT) system, involved in cilium assembly, and microtubule depolymerizing kinesins, which participate in cilium disassembly, play key roles in cilium length regulation. Additionally, several classes of kinases, including CDKL5, modify IFT components and/or depolymerizing kinesins to modulate ciliary length. We therefore hypothesized that the entire family of cyclin-dependent kinase-like (CDKL) proteins (CDKL1-5) may have similar ciliary functions. To test this hypothesis, we undertook studies in C. elegans. This nematode has one CDKL protein (CDKL-1) closely related to CDKL1-4 and more distantly related to CDKL5. We find that CDKL-1 localizes to cilia, including the transition zone (TZ), and negatively regulates cilium length by controlling IFT flux. Cilium length regulation by CDKL-1 is distinct from that of other kinases, namely DYF-18 (mammalian CCRK ortholog), DYF-5 (MAK) and NEKL-1 (NEK8/9). It also occurs independently from the depolymerizing kinesin-13 family, KLP-7 (KIF2A), which positively controls cilium length at the TZ. To query the molecular etiologies of human diseases caused by mutations in CDKL5 (epilepsy and atypical Rett syndrome) or KIF2A (brain malformations), we introduced corresponding patient mutations in C. elegans CDKL-1 and KLP-7, respectively. The mutations cause mislocalization and ciliary length defects. In addition, we find that disrupting C. elegans cdkl-1 results in sensory (CO2 avoidance) and developmental (body size) phenotypes, possibly resulting from anomalies in signaling pathway(s), including cGMP signaling. These data suggest that human ailments such as Rett syndrome and brain anomalies may arise from cilium length misregulation, and consequently, disruption of signaling pathways. In summary, our findings provide evidence that CDKL-1 works cooperatively with other kinases, and independently from a depolymerizing kinesin, to maintain correct ciliary length. Our work also suggests links between ciliary length control and potential ciliopathies, which provides potentially useful experimental avenues of exploration.