Mechanisms of chemosensory neuron cilia regeneration

PROJECT SUMMARY Primary non-motile cilia protrude from the cell surface of the majority of metazoan cells and act as cellular ‘antennae’ to sense and transduce environmental information. These organelles play a particularly critical role in sensory neurons such as olfactory neurons and photoreceptors. Specialized sensory neuron cilia

house all signal transduction molecules, and consequently, disruption of sensory cilia function as in ciliopathies is associated with anosmia, loss of vision, and impaired hearing. Since cilia are directly exposed to the environment, these structures are highly susceptible to damage by physical and chemical stimuli as well as

upon viral infection. Deciliation of olfactory neurons upon infection of sustentacular support cells by SARS- CoV-2 is associated with the rapid onset of anosmia characteristic of this viral disease. Although olfactory neuron cilia appear to partly regrow during recovery, the mechanisms regulating ciliary regeneration are

uncharacterized. Cilia/flagella in unicellular organisms have been shown to robustly regenerate following truncation, and this regeneration is mediated in part via transcriptional upregulation of ciliary genes. However, the mechanisms by which cilia growth state information is sensed and transduced to promote cilia regeneration

remains a major knowledge gap. In preliminary experiments, we have established conditions in which we can robustly induce chemosensory neuron cilia truncation and regeneration in individual sensory neuron types in C. elegans. We find that cilia regeneration requires a subset of conserved genes previously implicated in regulating axon

regeneration across species, and that moreover, induction of cilia regeneration is associated with upregulation of a ciliogenic gene. The overall goal of this exploratory R21 is to exploit the experimental amenability of C. elegans to identify the sensors, transducers, and effectors driving neuronal cilia regeneration and restoration of

chemosensory neuron functions. The specific goals are to: Aim 1. Characterize the contribution of molecules implicated in axon regeneration to chemosensory neuron cilia regrowth. Aim 2. Identify additional sensors, mediators, and effectors of cilia regrowth. Results from this exploratory work have the potential to identify new mechanisms by which cilia

regeneration is regulated in the nervous system, and how this regeneration is modulated as a function of neuron type. Given the conservation of ciliogenic mechanisms, this work may identify potential therapeutic strategies by which cilia structure and function can be restored following injury and infection across species.