Transient defects of mitotic spindle geometry and chromosome segregation errors

Mitosis, the process by which a single eukaryotic cell partitions its genetic material, has fascinated scientists for over a century, and already in the late 1800s Walther Flemming described the processes of chromosome segregation and cell division with exquisite detail [1,2]. Four main structures, consisting of centrosomes, a microtubule-based mitotic spindle, kinetochores, and chromosomes [3,4], cooperate to form the mitotic apparatus (Figure 1A) in vertebrate somatic cells. The centrosomes are specialized organelles, each consisting of a pair of centrioles and pericentriolar material, and they play a key role in mitotic spindle assembly by serving as the primary sites of microtubule nucleation [5,6]. Molecular motors act to move the replicated centrosomes to diametrically opposing positions around the nucleus [7-9] (Figure 1A, Prophase), thus ensuring assembly of a fusiform and symmetric microtubule-based mitotic spindle once the nuclear envelope breaks down. At the same time, within the nucleus, the chromosomes undergo significant condensation (Figure 1A, Prophase) while kinetochores assemble on the centromeric region of each sister chromatid of the replicated chromosomes (reviewed in [10]). Upon nuclear envelope breakdown, which marks the beginning of prometaphase, the kinetochores become available for capture by dynamically searching microtubules (Figure 1A, Prometaphase). The kinetochore is a large protein complex that constitutes the attachment site for microtubules of the mitotic spindle on each chromatid [11]. In addition to acting as attachment sites for microtubules, kinetochores are also part of a signaling pathway, termed the spindle assembly checkpoint (SAC), that facilitates the coordinated and accurate segregation of chromosomes by preventing anaphase onset until all kinetochores are bound to microtubules (reviewed in [12]). As mitosis progresses, chromosomes establish attachments with microtubules and undergo poleward and anti-poleward movements, w