title: CCM-3 Promotes C. elegans Germline Development by Regulating Vesicle Trafficking Cytokinesis and Polarity.
abstract: Cerebral cavernous malformations (CCMs) are vascular defects of the CNS that arise from loss of integrity of the endothelial cells lining blood capillaries, causing leakage of blood into the brain [1]. This results in headaches, seizures, and/or hemorrhagic stroke, depending on the location of the lesion. CCM affects 0.5% of the population and follows an autosomal dominant inheritance pattern caused by mutations in one of the three genes: CCM1 (gene name KRIT1), CCM2 (also known as malcavernin or OSM), and CCM3 (gene name PDCD10) [2, 3], with the earliest onset and most severe prognosis occurring in CCM3 patients [4]. The three CCM genes encode structurally distinct scaffold proteins that function in multiple complexes [5-9]. Using the C. elegans germline as a model of multicellular tube development, we show here that CCM-3 is enriched at the luminal membrane of the germline and the contractile ring of dividing cells in the embryo. Loss of ccm-3 results in defective RAB-11-mediated endocytic recycling, which in turn is necessary for gonadal lumen (rachis) formation, completion of cytokinesis, and localization of cell-surface receptors. CCM-3-mediated localization of anillin and non-muscle myosin to the lateral surfaces of germ cells is required for proper cytoskeletal organization, subsequent oocyte growth, and localization of polarity proteins. Biochemical analysis reveals conservation of the STRIPAK complex and distinct roles for GCK-1 (germinal center kinase III family protein) and striatin/CASH-1 in controlling the localization and function of CCM-3. Taken together, our data establish CCM-3 as a novel regulator of rachis lumenization and polarity establishment during embryogenesis.
authors.affiliation: Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
authors.forename: Swati
authors.initials: S
authors.lastname: Pal
authors.affiliation: Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lant
authors.affiliation: Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
authors.forename: Ruilin
authors.initials: R
authors.lastname: Tian
authors.affiliation: Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
authors.forename: Jiefei
authors.initials: J
authors.lastname: Tong
authors.affiliation: Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Krieger
authors.affiliation: Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Moran
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: brent.derry@sickkids.ca.
authors.forename: W Brent
authors.initials: WB
authors.lastname: Derry
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology*; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D048749:Cytokinesis / Q000235:genetics / Q000502:physiology*; D047108:Embryonic Development / Q000235:genetics*; D005854:Germ Cells / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport
chemical_list: D051017:Apoptosis Regulatory Proteins; C000627825:CCM-3 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins
keywords: CCM3; PDCD10; actin; anillin; cerebral cavernous malformations; endocytic recycling; lumen; myosin; polarity; tubulogenesis