Whole chromosome aneuploidy in the brain of Bub1bH/H and Ercc1-/Δ7 mice

Grasiella A. Andriani, Francesca Faggioli, Darren Baker, Martijn E T Dollé, Rani S. Sellers, Jean M. Hebert, Harry Van Steeg, Jan Hoeijmakers, Jan Vijg, Cristina Montagna

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

High levels of aneuploidy have been observed in disease-free tissues, including post-mitotic tissues such as the brain. Using a quantitative interphase-fluorescence in situ hybridization approach, we previously reported a chromosome-specific, age-related increase in aneuploidy in the mouse cerebral cortex. Increased aneuploidy has been associated with defects in DNA repair and the spindle assembly checkpoint, which in turn can lead to premature aging. Here, we quantified the frequency of aneuploidy of three autosomes in the cerebral cortex and cerebellum of adult and developing brain of Bub1b(H/H) mice, which have a faulty mitotic checkpoint, and Ercc1(-/Δ7) mice, defective in nucleotide excision repair and inter-strand cross-link repair. Surprisingly, the level of aneuploidy in the brain of these murine models of accelerated aging remains as low as in the young adult brains from control animals, i.e. <1% in the cerebral cortex and ∼0.1% in the cerebellum. Therefore, based on aneuploidy, these adult mice with reduced life span and accelerated progeroid features are indistinguishable from age-matched, normal controls. Yet, during embryonic development, we found that Bub1b(H/H), but not Ercc1(-/Δ7) mice, have a significantly higher frequency of aneuploid nuclei relative to wild-type controls in the cerebral cortex, reaching a frequency as high as 40.3% for each chromosome tested. Aneuploid cells in these mutant mice are likely eliminated early in development through apoptosis and/or immune-mediated clearance mechanisms, which would explain the low levels of aneuploidy during adulthood in the cerebral cortex of Bub1b(H/H) mice. These results shed light on the mechanisms of removal of aneuploidy cells in vivo.

Original languageEnglish (US)
Pages (from-to)755-765
Number of pages11
JournalHuman Molecular Genetics
Volume25
Issue number4
DOIs
StatePublished - Feb 15 2016

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Aneuploidy
Chromosomes
Brain
Cerebral Cortex
M Phase Cell Cycle Checkpoints
DNA Repair
Cerebellum
Premature Aging
Interphase
Fluorescence In Situ Hybridization
Embryonic Development
Young Adult
Apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Whole chromosome aneuploidy in the brain of Bub1bH/H and Ercc1-/Δ7 mice. / Andriani, Grasiella A.; Faggioli, Francesca; Baker, Darren; Dollé, Martijn E T; Sellers, Rani S.; Hebert, Jean M.; Van Steeg, Harry; Hoeijmakers, Jan; Vijg, Jan; Montagna, Cristina.

In: Human Molecular Genetics, Vol. 25, No. 4, 15.02.2016, p. 755-765.

Research output: Contribution to journalArticle

Andriani, GA, Faggioli, F, Baker, D, Dollé, MET, Sellers, RS, Hebert, JM, Van Steeg, H, Hoeijmakers, J, Vijg, J & Montagna, C 2016, 'Whole chromosome aneuploidy in the brain of Bub1bH/H and Ercc1-/Δ7 mice', Human Molecular Genetics, vol. 25, no. 4, pp. 755-765. https://doi.org/10.1093/hmg/ddv612
Andriani GA, Faggioli F, Baker D, Dollé MET, Sellers RS, Hebert JM et al. Whole chromosome aneuploidy in the brain of Bub1bH/H and Ercc1-/Δ7 mice. Human Molecular Genetics. 2016 Feb 15;25(4):755-765. https://doi.org/10.1093/hmg/ddv612
Andriani, Grasiella A. ; Faggioli, Francesca ; Baker, Darren ; Dollé, Martijn E T ; Sellers, Rani S. ; Hebert, Jean M. ; Van Steeg, Harry ; Hoeijmakers, Jan ; Vijg, Jan ; Montagna, Cristina. / Whole chromosome aneuploidy in the brain of Bub1bH/H and Ercc1-/Δ7 mice. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 4. pp. 755-765.
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