Cell division

Hold on and let go

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The discovery and functional analysis of the protein MEIKIN in mice leads to an evolutionarily conserved model of how chromosome segregation is regulated during a specialized type of cell division called meiosis I. See Article p.466

The movements of sister chromosomes during cell division can be compared to those of figure skaters on an ice rink. During most divisions, a pair of skaters stand back-to-back at the centre of the ice and, as the music starts, skate away from each other, separating forever. In a division that leads to the production of eggs or sperm, however, the two skaters stand side-by-side, back-to-back with another couple. Each couple holds hands as the two teams separate, and the skaters make their way across the ice together. Letting go of a partner too early could result in abnormal chromosome segregation and infertility, but the mechanisms that encourage chromosomes to hold on and separate together in this setting have long been a mystery. In this issue, Kim et al.1 (page 466) identify the first key regulator of this process in mammals, illuminating a molecular pathway that seems to be evolutionarily conserved from yeast to humans.

Cell division that produces two identical daughter cells is called mitosis. Before mitosis, each chromosome in the cell is duplicated to produce an identical sister — in humans, 46 chromosomes (23 pairs of 'homologous' chromosomes, one set from each parent) become 92. Duplicated chromosomes called sister chromatids are held together along chromosome arms and at specialized domains, the centromeres, by complexes of cohesin protein. Protein structures called kinetochores are built back-to-back (bi-oriented) on the centromeres of sister chromatids. Kinetochore bi-orientation facilitates sister-chromatid separation during the anaphase stage of division. At this time, cohesin is destroyed, and spindle fibres that extend from each pole of the cell attach to the facing kinetochore and pull sisters apart, partitioning an identical sister into each daughter cell (Fig. 1a).

Figure 1: Chromosome orientation in mitosis and meiosis.
figure1

Before cell division, identical chromosome copies called sister chromatids are held together by cohesin protein. How the chromatids segregate during division is determined by the orientation of protein structures called kinetochores — each chromatid is pulled towards the pole of the cell that the kinetochore faces (indicated by arrows). a, In mitosis, kinetochores sit back-to-back on sister chromatids (they are bi-oriented), and chromatids are pulled to opposite poles. b, In meiosis I, homologous chromosomes are linked as a consequence of meiotic recombination. The kinetochores of the homologous chromosomes face in opposite directions, but those of sister chromatids are mono-oriented and are pulled to the same cell pole.

By contrast, during meiosis, non-identical sperm or eggs (germ cells) are produced from two rounds of division, meiosis I and II. Meiosis follows chromosome duplication like mitosis, but DNA exchange, known as meiotic recombination, occurs between homologous chromosomes to ensure that germ cells have a mix of genetic material from each parent. Unlike mitosis, cohesin is maintained at centromeres during anaphase of meiosis I. Kinetochores on sister chromosomes face the same direction — they are mono-oriented — and are thus captured and pulled by spindle fibres from the same pole (Fig. 1b). Chromosome segregation in meiosis II proceeds in a similar manner to mitosis, separating the sisters into forming germ cells.

How kinetochore mono-orientation is regulated in meiosis I is a long-standing question. The only proteins known to regulate kinetochore orientation in meiosis specifically are Moa1 in fission yeast and Spo13 and Mam1 in budding yeast. However, the proteins from each species seem to show little genetic similarity to each other2,3,4,5, making it difficult to identify their mammalian counterparts. Building on the knowledge6 that Moa1 physically interacts with the kinetochore component protein Cnp3, Kim and colleagues used the equivalent mouse protein, CENP-C, as bait to fish out the corresponding mammalian kinetochore regulator, which they dub MEIKIN (for meiosis-specific kinetochore protein). MEIKIN is at the right place at the right time — located at kinetochores in meiosis I but undetectable in meiosis II.

The authors report that deletion of the Meikin gene in mice causes infertility in both sexes, consistent with a defect in meiosis. Tracking of wild-type oocytes (egg-precursor cells) in high spatial and temporal resolution showed that kinetochores of sister chromatids remain in close proximity shortly after anaphase I begins. By contrast, mono-oriented kinetochores split prematurely in MEIKIN-deficient oocytes, and sister chromosomes separate entirely before anaphase of meiosis II.

These results suggest that MEIKIN is directly or indirectly required to maintain cohesin at centromeres. Alternatively, cohesion between centromeres of MEIKIN-deficient oocytes may be only weakly generated in the first place. This is reminiscent of mutants with reduced cohesin gene expression7, in which centromere cohesion is abnormal in meiosis II. By inactivating MEIKIN at defined stages of meiosis, it may be possible to delineate whether the protein protects cohesin in anaphase I or is involved in earlier events.

Could MEIKIN regulate kinetochore mono-orientation? If so, why do kinetochores seem to mono-orient in its absence? In yeast, defects in mono-orientation can be obscured when chromosomes are physically linked as a consequence of meiotic recombination5. To circumvent this, kinetochore orientation can be analysed in mutant mice in which recombination does not occur. Recombination-deficient oocytes often arrest in meiosis I with mono-oriented kinetochores8. The authors demonstrate that, remarkably, loss of MEIKIN in such oocytes can lead to bi-orientation of kinetochores, enabling cell division. Therefore, MEIKIN facilitates kinetochore mono-orientation in addition to protecting centromeric cohesin.

How exactly MEIKIN regulates kinetochore orientation remains to be determined. The protein might help to physically fuse kinetochores together, or it could exert this effect indirectly, regulating as-yet-unidentified 'fusion proteins'. MEIKIN's location on kinetochores suggests that its mode of regulation is likely to be local. It is striking that loss of MEIKIN consistently delays meiosis I by several hours, which could reflect a need to halt the process until a threshold number of bi-oriented kinetochores is reached and a checkpoint is satisfied. However, it is unclear why this would take so long.

Experiments indicate9 that the timing defects observed by Kim et al. are more severe than those brought about by acute inactivation of centromeric cohesin, which also triggers sister-kinetochore bi-orientation in meiosis I. Therefore, MEIKIN might regulate the cell-cycle machinery. Indeed, Spo13 both promotes kinetochore mono-orientation and regulates APC/C, a protein complex that triggers anaphase3,4. Because mouse oocytes are ideal for quantifying the kinetics of APC/C activation, future work may address whether MEIKIN regulates the APC/C, and how this fits with its role at kinetochores.

Both functions ascribed to MEIKIN in this study — maintenance of centromeric cohesion and kinetochore mono-orientation — have previously been attributed to the enzyme PLK1 (refs 10, 11). Kim and colleagues provide evidence that MEIKIN and PLK1 function together. The proteins physically interact, and chemical inhibition of PLK1 has a similar effect to loss of Meikin. Furthermore, MEIKIN maintains normal levels of PLK1 at kinetochores. The authors find that this pathway is conserved in both budding and fission yeast, and that MEIKIN, Moa1 and Spo13 all act through a site that potentially binds PLK1 or its equivalent in yeast. It is this close collaboration that determines whether chromosomes hold on to 'skate' together or separately when the music starts.

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Correspondence to Kikuë Tachibana-Konwalski.

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Tachibana-Konwalski, K. Hold on and let go. Nature 517, 441–442 (2015). https://doi.org/10.1038/nature14087

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