title: A unique set of centrosome proteins requires pericentrin for spindle-pole localization and spindle orientation.
abstract: Majewski osteodysplastic primordial dwarfism type II (MOPDII) is caused by mutations in the centrosome gene pericentrin (PCNT) that lead to severe pre- and postnatal growth retardation. As in MOPDII patients, disruption of pericentrin (Pcnt) in mice caused a number of abnormalities including microcephaly, aberrant hemodynamics analyzed by in utero echocardiography, and cardiovascular anomalies; the latter being associated with mortality, as in the human condition. To identify the mechanisms underlying these defects, we tested for changes in cell and molecular function. All Pcnt(-/-) mouse tissues and cells examined showed spindle misorientation. This mouse phenotype was associated with misdirected ventricular septal growth in the heart, decreased proliferative symmetric divisions in brain neural progenitors, and increased misoriented divisions in fibroblasts; the same phenotype was seen in fibroblasts from three MOPDII individuals. Misoriented spindles were associated with disrupted astral microtubules and near complete loss of a unique set of centrosome proteins from spindle poles (ninein, Cep215, centriolin). All these proteins appear to be crucial for microtubule anchoring and all interacted with Pcnt, suggesting that Pcnt serves as a molecular scaffold for this functionally linked set of spindle pole proteins. Importantly, Pcnt disruption had no detectable effect on localization of proteins involved in the cortical polarity pathway (NuMA, p150(glued), aPKC). Not only do these data reveal a spindle-pole-localized complex for spindle orientation, but they identify key spindle symmetry proteins involved in the pathogenesis of MOPDII.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester MA.
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester MA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Hehnly
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh PA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh PA.
authors.forename: Debby
authors.initials: D
authors.lastname: Farkas
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester MA.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester MA.
authors.forename: Sambra D
authors.initials: SD
authors.lastname: Redick
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester MA.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Hung
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh PA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Samtani
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester MA.
authors.forename: Agata
authors.initials: A
authors.lastname: Jurczyk
authors.affiliation: Department of Psychiatry, University of Massachusetts Medical Center, Worcester MA.|Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York NY.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children.
authors.forename: Carol
authors.initials: C
authors.lastname: Wise
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh U.K.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Division of Genetics, Department of Pediatrics, A.I. Dupont Hospital for Children, Wilmington DE.
authors.forename: Michael
authors.initials: M
authors.lastname: Bober
authors.affiliation: Department of Psychiatry, University of Massachusetts Medical Center, Worcester MA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh PA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lo
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester MA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Doxsey
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics* / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism; D004195:Disease Models, Animal; D004392:Dwarfism / Q000235:genetics* / Q000503:physiopathology; D004622:Embryo, Mammalian / Q000196:embryology; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008831:Microcephaly / Q000235:genetics* / Q000503:physiopathology; D008870:Microtubules / Q000235:genetics*; D008938:Mitosis; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000503:physiopathology; D008941:Spindle Apparatus / Q000235:genetics* / Q000378:metabolism; D064047:Spindle Poles / Q000235:genetics / Q000378:metabolism
chemical_list: D000941:Antigens; C086178:pericentrin