Primary cilia are antenna-like projections that emanate from the cell surface of most quiescent mammalian cells. Cilia are essential for sensing extracellular cues and growth factors. They assemble from centrosomes and are resorbed in a cell cycle-dependent manner. Many questions remain regarding the mechanisms that provoke cilium assembly and disassembly. For example, links between reorganization of cytoskeletal proteins, tubulin modifications, and nuclear anchoring have emerged, but mechanistic connections to cilium assembly and disassembly are not well understood. We have begun characterizing key proteins required for ciliogenesis, including Talpid3, a protein known to play a role in signaling. Using proteome-wide methods to identify Talpid3- interaction partners, we isolated two previously uncharacterized proteins, LRRC49 and C11orf49, that play a potent role in suppressing inappropriate cilium assembly and maintaining both tubulin glutamylation and nuclear morphology. In two Aims that combine cell biological and biochemical approaches with gene-editing and use of an in vivo model, we will (1) investigate a role for LRRC49 and C11orf49 in timely cilium assembly and disassembly, (2) examine how LRRC49 and C11orf49 regulate nuclear morphology and cytoskeleton assembly and dynamics, and (3) test the broad biological roles of tubulin glutamylases and their connections to ciliogenesis, microtubule stability, and nuclear envelope assembly. By investigating the function of key proteins that regulate cilium assembly and disassembly, as well as control of cytoskeleton organization and nuclear shape in vitro and in vivo, we will address fundamental questions related to mammalian cell growth and cell cycle progression.
Primary cilia are antenna-like projections on the surface of quiescent and differentiated mammalian cells that play essential roles in mammalian growth and development. Defects in primary cilia underlie a spectrum of human diseases, birth defects, and cancer. This proposal will investigate the mechanisms required for cilium assembly and disassembly and their relationship to cytoskeletal organization through characterization of novel proteins identified in our laboratory.
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