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Centrosome amplification causes microcephaly

Nature Cell Biology volume 15, pages 731–740 (2013)Cite this article

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Abstract

Centrosome amplification is a hallmark of human tumours. In flies, extra centrosomes cause spindle position defects that result in the expansion of the neural stem cell (NSC) pool and consequently in tumour formation. Here we investigated the consequences of centrosome amplification during mouse brain development and homeostasis. We show that centrosome amplification causes microcephaly due to inefficient clustering mechanisms, where NSCs divide in a multipolar fashion producing aneuploid cells that enter apoptosis. Importantly, we show that apoptosis inhibition causes the accumulation of highly aneuploid cells that lose their proliferative capacity and differentiate, thus depleting the pool of progenitors. Even if these conditions are not sufficient to halt brain development, they cause premature death due to tissue degeneration. Our results support an alternative concept to explain the etiology of microcephaly and show that centrosome amplification and aneuploidy can result in tissue degeneration rather than overproliferation and cancer.

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Figure 1: Centrosome amplification in the developing CNS causes microcephaly.
Figure 2: Centrosome amplification does not impair neurogenesis.
Figure 3: Centrosome amplification does not cause spindle misorientation.
Figure 4: Centrosome amplification causes multipolar divisions.
Figure 5: Apoptosis in Plk4OE brains is p53 dependent.
Figure 6: Analysis of p53Plk4OE mutant brains.
Figure 7: Tissue degeneration and reduced lifespan on accumulation of aneuploid cells.

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Acknowledgements

We thank F. El Marjou, C. Daviaud, M. Garcia, V. Dangles-Marie, C. Marais and I. Grandjean for transgenesis and general mouse care; D. Vignjevic, S. Fre, F. Ubelmann, A. Simon, L. Stimmer, M. Bornens and J. Sillibourne for sharing reagents and knowledge; S. Robine for her motivation, knowledge and help, which were particularly important in the initial phases of this project; O. Leroy for advice on 3D reconstructions; L. Sengmanivong, F. Waharte, V. Fraisier, O. Renaud and the Nikon imaging facility at the I. Curie for valuable help and advice with image acquisition; E. Nora, K. Ancelin, M. Attia and E. Heard for advise on DNA FISH; A. Bardin, N. Delgehyr, F. Gergely, I. Kazanis, M. Rujano, F. Bosveld and T. Maia for discussions and comments on the manuscript. We thank FRM and La Ligue contre le Cancer for financial support (V.M.). This work was supported by an ERC grant CentroStemCancer 242598, an FRM installation grant, an ATIP grant, the Institut Curie and the CNRS.

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Authors and Affiliations

  1. UMR144, CNRS-Institut Curie, 12 rue Lhomond, 75005 Paris, France

    Véronique Marthiens, Maria A. Rujano, Carole Pennetier, Sarah Tessier, Perrine Paul-Gilloteaux & Renata Basto

  2. Cell and Tissue Imaging Facility (PICT-IBiSA), UMR 144, CNRS-Institut Curie, 75005 Paris, France

    Perrine Paul-Gilloteaux

Authors
  1. Véronique Marthiens
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  2. Maria A. Rujano
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Contributions

V.M and R.B conceived the project. V.M carried out most of the experimental procedures. M.A.R. performed the time-lapse experiments and together with S.T. and P.P-G. helped with data analysis. C.P. performed the genotyping and generated reagents. V.M analysed most of the data with help from R.B. V.M. and R.B. wrote the manuscript. R.B. supervised the project.

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Correspondence to Renata Basto.

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Marthiens, V., Rujano, M., Pennetier, C. et al. Centrosome amplification causes microcephaly. Nat Cell Biol 15, 731–740 (2013). https://doi.org/10.1038/ncb2746

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