Cilia are microtubule-based organelles that emanate from the surface of most mammalian cell types. Motile cilia have well known roles in producing flow, while non-motile cilia play important sensory/signalling roles. Both forms are based on a similar axonemal structure, but ciliary motility requires additional components that conform to a regular arrangement along microtubules thought to be dictated by the protofilament ribbon (pf-ribbon). While pf-ribbon proteins have been implicated in ciliary motility, sensory/signalling functions in non-motile cilia have been less apparent. Although the ciliated organism Caenorhabditis elegans lacks motile cilia, orthologues of several ciliary pf-ribbon-associated proteins are present, including PACRG (Parkin co-regulated gene) and EFHC1 (EF-hand containing 1). In addition to their localisation to motile cilia, the pf-ribbon proteins show expression in neuronal cells of the brain where they may play important sensory roles. In particular, EFHC1 is mutated in the most common form of inherited epilepsy in humans and has been shown to be important for proper neuronal communication. This work investigates these motility-associated genes in C. elegans to dissect their sensory/signalling roles. We find that both PCRG-1 and EFHC-1 localise to a small subset of non-motile cilia in C. elegans, suggesting that they have been adapted to mediate specific sensory/signalling functions. We show that PCRG-1 influences a learning behaviour known as gustatory plasticity, where it is functionally coupled to heterotrimeric G-protein signalling. We also demonstrate that PCRG-1 promotes longevity in C. elegans by acting upstream of the lifespan-promoting FOXO transcription factor DAF-16 and likely upstream of insulin/IGF signalling, and that EFHC-1 also promotes longevity, suggesting shared signalling functions for these proteins. In addition, EFHC-1 modulates dopamine signalling where it is required for ciliary mechanosensation and regulating synaptic release of dopamine in cooperation with a voltage-gated calcium channel. Our findings establish previously unrecognised sensory/signalling functions for both PACRG and EFHC1 that may be important for neuronal communication in the human brain, where both proteins are known to be present. Furthermore, our work provides important clues for understanding and ultimately providing novel avenues for intervention of disorders such as epilepsy.
Copyright is held by the author.
This thesis may be printed or downloaded for non-commercial research and scholarly purposes.
Supervisor or Senior Supervisor
Thesis advisor: Leroux, Michel R.
Member of collection