title: Ciliopathy-associated gene Cc2d2a promotes assembly of subdistal appendages on the mother centriole during cilia biogenesis.
abstract: The primary cilium originates from the mother centriole and participates in critical functions during organogenesis. Defects in cilia biogenesis or function lead to pleiotropic phenotypes. Mutations in centrosome-cilia gene CC2D2A result in Meckel and Joubert syndromes. Here we generate a Cc2d2a(-/-) mouse that recapitulates features of Meckel syndrome including embryonic lethality and multiorgan defects. Cilia are absent in Cc2d2a(-/-) embryonic node and other somatic tissues; disruption of cilia-dependent Shh signalling appears to underlie exencephaly in mutant embryos. The Cc2d2a(-/-) mouse embryonic fibroblasts (MEFs) lack cilia, although mother centrioles and pericentriolar proteins are detected. Odf2, associated with subdistal appendages, is absent and ninein is reduced in mutant MEFs. In Cc2d2a(-/-) MEFs, subdistal appendages are lacking or abnormal by transmission electron microscopy. Consistent with this, CC2D2A localizes to subdistal appendages by immuno-EM in wild-type cells. We conclude that CC2D2A is essential for the assembly of subdistal appendages, which anchor cytoplasmic microtubules and prime the mother centriole for axoneme biogenesis.
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Shobi
authors.initials: S
authors.lastname: Veleri
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Souparnika H
authors.initials: SH
authors.lastname: Manjunath
authors.affiliation: Biological Imaging Core, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Fariss
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: May-Simera
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brooks
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Foskett
authors.affiliation: Biological Imaging Core, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Gao
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Longo
authors.affiliation: Genetic Engineering Core, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Pinghu
authors.initials: P
authors.lastname: Liu
authors.affiliation: Electron Microscope Laboratory, Advanced Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, USA.
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Rivka A
authors.initials: RA
authors.lastname: Rachel
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Tiansen
authors.initials: T
authors.lastname: Li
authors.affiliation: Genetic Engineering Core, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Lijin
authors.identifier: 0000000219751141
authors.initials: L
authors.lastname: Dong
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
mesh_terms: D000483:Alleles; D000818:Animals; D001692:Biological Transport; D002502:Centrioles / Q000378:metabolism*; D018385:Centrosome / Q000648:ultrastructure; D002923:Cilia / Q000235:genetics / Q000473:pathology*; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D053823:Hedgehog Proteins / Q000378:metabolism; D008253:Macaca mulatta; D051379:Mice; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D016253:Microscopy, Immunoelectron; D008870:Microtubules / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction; D019076:Transgenes
chemical_list: C000599986:CC2D2A protein, mouse; D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; D011506:Proteins; C465570:Shh protein, mouse