A Unique Set of Centrosome Proteins Requires Pericentrin for Spindle-Pole Localization and Spindle Orientation

Chun Ting Chen, Heidi Hehnly, Qing Yu, Debby Farkas, Guoqiang Zheng, Sambra D. Redick, Hui Fang Hung, Rajeev Samtani, Agata Jurczyk, Schahram Akbarian, Carol Wise, Andrew Jackson, Michael Bober, Yin Guo, Cecilia Lo, Stephen Doxsey

Research output: Contribution to journalArticle

48 Scopus citations

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 [1]. 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 [1]. 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, p150glued, 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.

Original languageEnglish (US)
Pages (from-to)2327-2334
Number of pages8
JournalCurrent Biology
Volume24
Issue number19
DOIs
StatePublished - Oct 6 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Chen, C. T., Hehnly, H., Yu, Q., Farkas, D., Zheng, G., Redick, S. D., Hung, H. F., Samtani, R., Jurczyk, A., Akbarian, S., Wise, C., Jackson, A., Bober, M., Guo, Y., Lo, C., & Doxsey, S. (2014). A Unique Set of Centrosome Proteins Requires Pericentrin for Spindle-Pole Localization and Spindle Orientation. Current Biology, 24(19), 2327-2334. https://doi.org/10.1016/j.cub.2014.08.029