title: Ccdc11 is a novel centriolar satellite protein essential for ciliogenesis and establishment of left-right asymmetry.
abstract: The establishment of left-right (L-R) asymmetry in vertebrates is dependent on the sensory and motile functions of cilia during embryogenesis. Mutations in CCDC11 disrupt L-R asymmetry and cause congenital heart disease in humans, yet the molecular and cellular functions of the protein remain unknown. Here we demonstrate that Ccdc11 is a novel component of centriolar satellites-cytoplasmic granules that serve as recruitment sites for proteins destined for the centrosome and cilium. Ccdc11 interacts with core components of satellites, and its loss disrupts the subcellular organization of satellite proteins and perturbs primary cilium assembly. Ccdc11 colocalizes with satellite proteins in human multiciliated tracheal epithelia, and its loss inhibits motile ciliogenesis. Similarly, depletion of CCDC11 in Xenopus embryos causes defective assembly and motility of cilia in multiciliated epidermal cells. To determine the role of CCDC11 during vertebrate development, we generated mutant alleles in zebrafish. Loss of CCDC11 leads to defective ciliogenesis in the pronephros and within the Kupffer's vesicle and results in aberrant L-R axis determination. Our results highlight a critical role for Ccdc11 in the assembly and function of motile cilia and implicate centriolar satellite-associated proteins as a new class of proteins in the pathology of L-R patterning and congenital heart disease.
authors.affiliation: Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Erica
authors.initials: E
authors.lastname: Silva
authors.affiliation: Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Betleja
authors.affiliation: Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Emily
authors.initials: E
authors.lastname: John
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Philip
authors.initials: P
authors.lastname: Spear
authors.affiliation: Department of Chemical Biology, Scripps Research Institute, La Jolla, CA 92037.
authors.forename: James J
authors.initials: JJ
authors.lastname: Moresco
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Siwei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Chemical Biology, Scripps Research Institute, La Jolla, CA 92037.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Mitchell
authors.affiliation: Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 mmahjoub@dom.wustl.edu.
authors.forename: Moe R
authors.initials: MR
authors.lastname: Mahjoub
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002502:Centrioles / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism; D002923:Cilia / Q000378:metabolism / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047108:Embryonic Development / Q000502:physiology; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009024:Morphogenesis / Q000502:physiology; D017384:Sequence Deletion; D014981:Xenopus; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C000602814:CFAP53 protein, human; C000602974:CFAP53 protein, zebrafish; D003598:Cytoskeletal Proteins; D029961:Zebrafish Proteins