Cilia are essential organelles, with functions ranging from cell-cell signaling to the generation of homeostatic fluid flow in tubular organs. Consequently, an array of human congenital diseases has been characterized as ?ciliopathies,? because they share an etiology of defective cilia structure or function. Despite manifest roles in the disruption of the central nervous system, limbs, axial skeleton, kidneys, airway, brain, and reproductive tracts, our understanding of the mechanisms that govern ciliogenesis and cilia-mediated developmental patterning remain incomplete. We propose here to study the roles of a novel multi-protein complex that controls three crucial mechanisms: basal body docking, IntraFlagellar Transport (IFT) recruitment, and Planar Cell Polarity (PCP). We will do so using a combination of proteomics, in vivo cell biology, mouse genetics and human disease modeling. By focusing on proteins with demonstrated importance in development and disease, but for which no mechanism of action is yet known, experiments proposed here will provide important new breadth and depth to our understanding cilia-mediated developmental patterning, basal body docking, and novel cell biological processes in ciliary biology. In turn, these findings should provide greater insight to a range of congenital diseases including both the relatively mild Oral-Facial-Digital syndrome and the wholly lethal Short Rib Polydactyly.
All vertebrate cells make a complex cellular structure?essential for embryonic development?called the cilium, defects in which underlie congenital birth defects known as ciliopathies. Many ciliopathies, including Oral- Facial-Digital syndrome, Joubert syndrome, Meckel-Gruber syndrome, and the 100% lethal Short Rib Polydactyly, arise from mutations in a particular set of genes that are critical for proper cilia formation, but which are nonetheless still poorly characterized. This grant proposes mass spectrometry proteomics, systems biology, cell biology, and experimental analysis of human disease allels to understand the mechanistic basis by which these genes work together to effect proper cilium formation, and how specific mutations in these genes lead to specific birth defects.
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