PT  - JOURNAL ARTICLE
AU  - Vanessa Nunes
AU  - Margarida Dantas
AU  - Elisa Vitiello
AU  - Irene Wang
AU  - Nicolas Carpi
AU  - Martial Balland
AU  - Matthieu Piel
AU  - Paulo Aguiar
AU  - Helder Maiato
AU  - Jorge G Ferreira
TI  - Spatial Asymmetries of the Prophase Nucleus Regulate Dynein Recruitment to Ensure Mitotic Fidelity
AID  - 10.1101/526939
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 526939
4099  - http://biorxiv.org/content/early/2019/01/21/526939.short
4100  - http://biorxiv.org/content/early/2019/01/21/526939.full
AB  - Accurate chromosome segregation during mitosis requires the efficient assembly of a microtubule-based structure known as the mitotic spindle. To achieve this, most cells rely on centrosomes, which must separate to establish a bipolar configuration. Several molecular components are involved in centrosome movement but how their activities are coordinated in space and time remains unknown. Here, we provide an integrated mechanistic view that explains how cell geometry influences centrosome positioning and investigate the respective consequences for spindle assembly and mitotic fidelity. We demonstrate that the initial axis of centrosome separation depends on cytoskeletal tension and cortical Dynein distribution. As mitotic cells round up and tension decreases, the centrosomes and nucleus reorient so that centrosomes are positioned on the short nuclear axis during nuclear envelope breakdown (NEB). We demonstrate how mitotic chromosome condensation creates a stiffness asymmetry on the prophase nucleus to enable polarized Dynein loading on the nuclear envelope (NE), thus ensuring correct centrosome positioning. We further show that Dynein polarization, but not loading, depends on an intact microtubule network and nuclear lamina. Finally, we show that centrosome positioning on the short nuclear axis is relevant for the fidelity of chromosome segregation. These results demonstrate how Dynein recruitment is mechanically regulated to ensure accurate chromosome segregation.