The role of a cilium assembly subnetwork at the basal body-vesicle membrane interface

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Primary cilia are cellular antennae' that extend out of the cell and mediate critical signaling pathways. A cilium consists of a microtubular shaft which is rooted at the basal body, and surrounded by a specialized membrane that is concentrated with receptors to correctly interpret diverse extracellular cues. Ciliary defects lead to large spectrum of diseases. These include polycystic kidney disease, retinal degeneration and congenital heart defects, and the loss of this organelle may be a key event during cancer progression. The long term objective of my research is to understand how the ciliary membrane and underlying structures are assembled and maintained. While many of the constituents of this organelle have been identified, it is unclear how these proteins interact with each other or with the cellular milieu for their function. The current proposal is designed to understand how a novel network of proteins - COMMD/WASH - that sort cargo from membranes is involved during cilium formation. We found this complex in a large proteomic study, and we have evidence that it associates with components of the basal body known to associate with the nascent ciliary membrane. We also have data indicating that it is required for cells to produce normal cilia. We will use gene disruption, super-resolution microscopy and proteomics to study : 1) which components of this complex are required for ciliation; 2) which exact step of ciliation is affected by these components; 3) how the cargo sorting function of this complex affects the ciliary membrane. We will leverage this knowledge to understand, at a molecular level, how the proteins at the basal body interface with membranes during cilium formation, so as to produce a functioning ciliary membrane. In doing so, we will provide fundamental insights to help understand, not only cellular growth and signalling, but also how to better treat human disease. The proposed research program will train three graduate students and multiple undergraduate associates in fundamental cell and molecular genetic methods, as well as in cutting-edge new approaches in proteomics and functional genomics. This training will propel the next generation of Canadian scientists in their careers. For these reasons, this research has long-term benefits to Canada's health and knowledge economies, as well as to Canadians at large.