RT Journal Article
SR Electronic
T1 Spatial Asymmetries of the Prophase Nucleus Regulate Dynein Recruitment to Ensure Mitotic Fidelity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 526939
DO 10.1101/526939
A1 Vanessa Nunes
A1 Margarida Dantas
A1 Elisa Vitiello
A1 Irene Wang
A1 Nicolas Carpi
A1 Martial Balland
A1 Matthieu Piel
A1 Paulo Aguiar
A1 Helder Maiato
A1 Jorge G Ferreira
YR 2019
UL http://biorxiv.org/content/early/2019/01/21/526939.abstract
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.