Regeneration and regrowth of sensory cilia via non-canonical mechanisms

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DESCRIPTION (provided by applicant): Primary cilia are microtubule-based sensory organelles that are now known to be present on nearly all cell types in humans and other metazoans. Cilia house signaling molecules and are required to accurately sense and transduce environmental stimuli. Cilia are particularly critical for the sensory functions of peripheral chem-, mechano- and photo-sensory neurons. For instance, olfactory signaling proteins are concentrated in the cilia that emanate from the dendritic knob of olfactory sensory neurons. Disruption of olfactory cilia results in anosmia. Similarly, loss of kinocilia in the inner ear reslts in defects in the organization of the stereocilia bundle leading to hearing anomalies. Ciliary dysfunction underlies a range of disorders and diseases collectively referred to as ciliopathies. Ciliogenic mechanisms are highly conserved across species, and insights from model organisms such as C. elegans and Chlamydomonas have been instrumental in defining molecules and mechanisms required for cilia structure and function. A subset of sensory neurons in C. elegans is ciliated and as in their vertebrate counterparts, these cilia contain signaling molecules and are essential for sensory transduction. All cilia are formed by the highly conserved process of intraflagellar transport or IFT; loss of IFT gene function results in severe ciliary structural defects. We made the surprising observation that cilia-like processes regenerate and regrow upon aging in a subset of chemosensory neurons in C. elegans lacking IFT gene function. These processes resemble bona fide cilia since they house ciliary proteins and partly restore chemosensory functions to the sensory neurons. We hypothesize that aging induces ciliary regrowth or regeneration via partly non- canonical ciliogenic mechanisms in C. elegans. The overall goal of this exploratory R21 proposal is to further investigate the mechanisms of this previously undescribed regeneration process. The Specific Aims are to: 1) Describe the structure and function of regenerated cilia-like structures in IFT mutants. Experiments proposed in this aim will investigate the extent to which the structure and function of the regenerated cilia-like structures in aged IFT mutants resemble those of cilia present in age-matched wild-type animals. 2) Investigate the mechanisms required for regrowth of cilia-like structures in aged IFT mutants. Experiments proposed in this aim will investigate the mechanisms by which regrowth of the cilia-like structures is triggered in aging animals, as well as identify the molecules and pathways which mediate the regrowth. Results from this work will provide the framework for the design of future experiments aimed at further characterizing this previously undescribed phenomenon of age-regulated ciliary regrowth in the absence of core IFT gene function. Since ciliogenic mechanisms are remarkably conserved across phyla, we expect that our findings will have major implications on our knowledge of cilia generation and maintenance, and may suggest new avenues and strategies to target ciliopathies and sensory neuron dysfunction.