Spatio-Temporal Regulation of Mitotic Spindle Checkpoints

Abstract

Stable microtubule spindle attachments at the kinetochores (KT) - the microtubule binding platform on the chromosome - ensure faithful chromosome segregation in mitosis. Unstable KT-spindle attachment locally activates the spindle assembly checkpoint (SAC) - an inhibitory signal that halts mitotic progression of the entire cell. Only after the last KT gets properly attached, can SAC get silenced and chromosome segregation ensue. However, given the everlasting stochastic fluctuations and large chromosome number in the cell, the mechanism ensuring the robustness in the SAC silencing timing remains elusive. From the stably attached KT, key mitotic players, including SAC, stream toward the associated spindle pole. Incorporating such spatial-temporal regulation, we established a theoretical model that unprecedentedly accounted for the fidelity of SAC silencing. It revealed that spindle poles integrate the poleward streaming from the attached KTs. The unattached KTs divert the poleward streaming, competing with the spindle poles. The diversion disappears upon the last KT-spindle attachment, causing a larger jump in the spindle pole accumulation than all the previous KT-spindle attachments combined. This large jump robustly triggers SAC silencing from the spindle poles after and only after the last KT-spindle attachment. This mechanistic insight accounts for many intriguing observations on mitosis, including the biphasic taxol dosage-dependence of anaphase delay, the distinct SAC silencing patterns in merged cells with two spindles, the size scaling between the mitotic spindle and the cell, and the error-proneness of mammalian oocyte meiosis. We thus established a unified conceptual framework across species - the spatial-temporal regulation ensures the fidelity of SAC silencing.