Many sensory neurons contain nnicrotubule-based structures called primary cilia which exhibit highly specialized and unique morphologies. Sensory cilia house signaling molecules, and their complex structures are essential for signal transduction. Little is known about the mechanisms by which ciliary structural diversity is generated and maintained. A subset of sensory neurons in C. elegans is ciliated, and many of these neurons exhibit elaborate ciliary architecture. The overall goal of this proposal is to characterize the mechanisms that generate and maintain cell-specific specialized cilia. In work funded by this grant, we have identified and characterized multiple mechanisms underlying the generation of unique ciliary structures in C. elegans. We showed that cilia morphology is sculpted via a tight balance between membrane delivery and retrieval by exocytic and endocytic mechanisms, identified several new molecules required for ciliogenesis in a defined subset of sensory neurons, showed that the roles of at least one of these molecules in regulating ciliogenesis is conserved in mammals, identified diverse molecular mechanisms that act in a protein- and cell-specific manner to traffic ciliary transmembrane proteins, and completed an exhaustive compendium of the ultrastructures, and reconstructions of 3D structures, of 50 of 60 C. elegans sensory cilia at high resolution using serial section electron microscopy and tomography. In the next funding period we propose to: 1) Characterize the role of the conserved multidomain cytoskeietal protein Girdin in regulating ciliogenesis in C. elegans and mammalian cells, 2) Investigate the function ofthe non-canonical MAP kinase MAPK15/ERK8 in specialized cilia formation, and 3) Identify new mechanisms of ciliary protein trafficking and microtubule dynamics via characterization of molecules that regulate the complex ciliary arborization of a sensory neuron type. Ciliary dysfunction is causal to a plethora of cellular and systemic disorders called ciliopathies. Given the remarkable conservation of ciliogenic mechanisms across species, results from this work are expected to lead to new insights into potential therapeutic strategies to target these disorders.
Primary cilia are specialized structures that are present on many cell types and that maintain cellular and organismal function. Ciliary dysfunction results in a range of disorders called ciliopathies. The molecules required for cilia formation and function are highly conserved. We will identify and characterize genes required for cilia formation in the model system C. elegans. Insights from this work will be directly relevant to our tinderstandinn of cilia structure and function in both normal and disease states
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