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.

Public Health Relevance

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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZRG1)
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Coulombe, James N
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University of Texas Austin
Schools of Arts and Sciences
United States
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Akhmetov, Azat; Laurent, Jon M; Gollihar, Jimmy et al. (2018) Single-step Precision Genome Editing in Yeast Using CRISPR-Cas9. Bio Protoc 8:
Akhmetov, Azat; Ellington, Andrew D; Marcotte, Edward M (2018) A highly parallel strategy for storage of digital information in living cells. BMC Biotechnol 18:64
Verbeke, Eric J; Mallam, Anna L; Drew, Kevin et al. (2018) Classification of Single Particles from Human Cell Extract Reveals Distinct Structures. Cell Rep 24:259-268.e3
Bruel, Ange-Line; Franco, Brunella; Duffourd, Yannis et al. (2017) Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes. J Med Genet 54:371-380
Mallam, Anna L; Marcotte, Edward M (2017) Systems-wide Studies Uncover Commander, a Multiprotein Complex Essential to Human Development. Cell Syst 4:483-494
Khokha, Mustafa K; Mitchell, Laura E; Wallingford, John B (2017) An opportunity to address the genetic causes of birth defects. Pediatr Res 81:282-285
Butler, Mitchell T; Wallingford, John B (2017) Planar cell polarity in development and disease. Nat Rev Mol Cell Biol 18:375-388
Tabler, Jacqueline M; Rigney, Maggie M; Berman, Gordon J et al. (2017) Cilia-mediated Hedgehog signaling controls form and function in the mammalian larynx. Elife 6:
Toriyama, Manami; Toriyama, Michinori; Wallingford, John B et al. (2017) Folate-dependent methylation of septins governs ciliogenesis during neural tube closure. FASEB J 31:3622-3635
Kachroo, Aashiq H; Laurent, Jon M; Akhmetov, Azat et al. (2017) Systematic bacterialization of yeast genes identifies a near-universally swappable pathway. Elife 6:

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