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J Cell Biol. 2018 Oct 1;217(10):3416-3430. doi: 10.1083/jcb.201806072. Epub 2018 Aug 6.

Chromosome structural anomalies due to aberrant spindle forces exerted at gene editing sites in meiosis.

Author information

1
Collège de France, Centre for Interdisciplinary Research in Biology, UMR CNRS 7241/INSERM-U1050, Paris, France.
2
Institut Curie, Paris Sciences et Lettres Research University, Centre National de la Recherche Scientifique, UMR144, Biology of Centrosomes and Genetic Instability Laboratory, Paris, France.
3
Biological Science, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK.
4
Collège de France, Centre for Interdisciplinary Research in Biology, UMR CNRS 7241/INSERM-U1050, Paris, France marie-helene.verlhac@college-de-france.fr.

Abstract

Mouse female meiotic spindles assemble from acentriolar microtubule-organizing centers (aMTOCs) that fragment into discrete foci. These are further sorted and clustered to form spindle poles, thus providing balanced forces for faithful chromosome segregation. To assess the impact of aMTOC biogenesis on spindle assembly, we genetically induced their precocious fragmentation in mouse oocytes using conditional overexpression of Plk4, a master microtubule-organizing center regulator. Excessive microtubule nucleation from these fragmented aMTOCs accelerated spindle assembly dynamics. Prematurely formed spindles promoted the breakage of three different fragilized bivalents, generated by the presence of recombined Lox P sites. Reducing the density of microtubules significantly diminished the extent of chromosome breakage. Thus, improper spindle forces can lead to widely described yet unexplained chromosomal structural anomalies with disruptive consequences on the ability of the gamete to transmit an uncorrupted genome.

PMID:
30082296
PMCID:
PMC6168266
DOI:
10.1083/jcb.201806072
[Indexed for MEDLINE]
Free PMC Article

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