Journal
BLOOD
Volume 120, Issue 18, Pages 3803-3811Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-03-419663
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Funding
- Wellcome Trust
- Royal Society University Research Fellowship
- Dorothy Hodgkin fellowship from the Royal Society
- Great Ormond Street Children's Charity
- Great Ormond Street Hospital Childrens Charity [V1259, V1223] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10001] Funding Source: researchfish
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The constitutively active mutant of the Wiskott-Aldrich Syndrome protein (CA-WASp) is the cause of X-linked neutropenia and is linked with genomic instability and myelodysplasia. CA-WASp generates abnormally high levels of cytoplasmic F-actin through dysregulated activation of the Arp2/3 complex leading to defects in cell division. As WASp has no reported role in cell division, we hypothesized that alteration of cell mechanics because of increased F-actin may indirectly disrupt dynamic events during mitosis. Inhibition of the Arp2/3 complex revealed that excess cytoplasmic F-actin caused increased cellular viscosity, slowed all phases of mitosis, and perturbed mitotic mechanics. Comparison of chromosome velocity to the cytoplasmic viscosity revealed that cells compensated for increased viscosity by up-regulating force applied to chromosomes and increased the density of microtubules at kinetochores. Mitotic abnormalities were be-cause of overload of the aurora signaling pathway as subcritical inhibition of Aurora in CA-WASp cells caused increased cytokinesis failure, while overexpression reduced defects. These findings demonstrate that changes in cell mechanics can cause significant mitotic abnormalities leading to genomic instability, and highlight the importance of mechanical sensors such as Aurora B in maintaining the fidelity of hematopoietic cell division. (Blood.2012;120(18):3803-3811)
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