Research Article

Actin protects mammalian eggs against chromosome segregation errors

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Science  25 Aug 2017:
Vol. 357, Issue 6353, eaal1647
DOI: 10.1126/science.aal1647

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Actin helps chromosome segregation in eggs

Spindle microtubules are well known to orchestrate the segregation of chromosomes during egg development. But the other major cytoskeletal component, actin, has not been thought to play a role in this process. Mogessie and Schuh examined how chromosomes are segregated in mammalian cells (see the Perspective by Maiato and Ferrás). Instead of using an entirely microtubule-dependent mechanism, mammalian oocytes use a second spindle that is made of F-actin to segregate their chromosomes correctly. Actin associated with the spindle bundles microtubules into functional kinetochore fibers, the key structures that drive chromosome segregation. Increasing or decreasing the number of actin filaments in the spindle causes an imbalance in kinetochore fiber bundling, which results in chromosome segregation errors and aneuploidy, a frequent cause of miscarriage and Down syndrome in humans.

Science, this issue p. eaal1647; see also p. 756

Structured Abstract


When an egg is fertilized by a sperm, the chromosomes of the mother and the father become united, and a genetically unique embryo starts to form. A healthy embryo can only develop if both the egg and the sperm contain precisely one copy of each chromosome. However, human eggs frequently contain an incorrect number of chromosomes. Fertilization of these aneuploid eggs is a leading cause of miscarriages, infertility, and Down syndrome. Most aneuploidy results from chromosome segregation errors during the meiotic divisions of the egg. Chromosome segregation is well established to be driven by a spindle that consists of microtubules. The microtubules first capture and align the chromosomes at the spindle center. During anaphase, the spindle segregates the chromosomes and moves them to the spindle poles. The movement of chromosomes is driven by the shortening of microtubule bundles that are attached to the chromosomes’ kinetochores, called kinetochore fibers (K-fibers). Although actin has been reported in spindles of various species, it is generally not thought to be involved in chromosome segregation.


We found prominent actin filaments in spindles of human, mouse, porcine, and ovine eggs. The filaments permeated the entire spindle volume and formed structures that resembled a microtubule spindle. The wide conservation of spindle actin suggested that it has an essential function, which we set out to investigate. We visualized spindle actin organization in mouse eggs using superresolution imaging of fluorescently labeled actin, microtubules, and chromosomes in living and fixed cells. We then investigated the function of spindle actin by either depleting actin from the spindle or increasing the amount of actin in the spindle. To deplete spindle actin, we used eggs that lacked formin-2, the actin nucleation factor that is required to form spindle actin, and treated eggs with an actin-depolymerizing drug. To increase spindle actin, we targeted a protein domain to the spindle that stabilizes actin filaments. We then imaged chromosomes and the spindle at high spatial and temporal resolution throughout the first and second meiotic division and quantified defects. We also investigated potential defects in spindle organization, including the dynamics of microtubules in the spindle and the formation and bundling of K-fibers, using a combination of quantitative assays in live and fixed eggs.


Spindle actin assembled gradually during the first meiotic division in mouse oocytes and became most prominent when the chromosomes segregated during anaphase: Dense, long actin bundles that spanned the entire spindle length permeated the microtubule spindle throughout anaphase. Unexpectedly, we found that eggs that lacked actin were more likely to suffer from chromosome segregation errors during both the first and second meiotic division. Actin-depleted eggs took longer to align their chromosomes and frequently contained chromosomes that were trapped at the spindle poles or oscillated within the spindle. Also, the acute addition of actin-disrupting drugs to spindles in which the chromosomes had already been aligned led to displacement of chromosomes from the spindle center. When chromosomes were segregated during anaphase, individual chromosomes were frequently lagging behind the main masses of chromosomes, and the overall speed of chromosome movement was reduced. Actin is likely to facilitate chromosome alignment and segregation by promoting the formation of K-fibers because K-fibers were reduced when spindle actin was absent. Consistent with this model, increasing the amount of actin in the spindle led to an increase in K-fibers as well as defects in chromosome alignment and segregation.


That actin drives the formation of K-fibers was unexpected because K-fibers are generally thought to be formed by microtubule-associated proteins and kinetochore components independently of actin. Our data therefore highlight a previously unknown mechanism of how K-fibers are generated in mammalian eggs. Mammalian eggs are highly prone to chromosome segregation errors, which are a leading cause of miscarriages and genetic disorders such as Down syndrome. Understanding the mechanisms that drive chromosome segregation in mammalian eggs is therefore particularly important. The presence of spindle actin in other mammalian eggs, including humans, hints at a conserved function in chromosome segregation. This function may even extend beyond mammals because actin filaments have been reported in spindles of a variety of species and cell types.

Spindle actin in a mouse egg.

Microtubule spindles in mammalian eggs are permeated by actin filaments (blue). Actin filaments are essential for the accurate alignment and segregation of chromosomes (magenta) during meiosis because they promote the formation of K-fibers. K-fibers are specialized microtubule fibers within the spindle that attach to the chromosomes’ kinetochores and mediate chromosome segregation.


Chromosome segregation is driven by a spindle that is made of microtubules but is generally thought to be independent of actin. Here, we report an unexpected actin-dependent mechanism that drives the accurate alignment and segregation of chromosomes in mammalian eggs. Prominent actin filaments permeated the microtubule spindle in eggs of several mammalian species, including humans. Disrupting actin in mouse eggs led to significantly increased numbers of misaligned chromosomes as well as lagging chromosomes during meiosis I and II. We found that actin drives accurate chromosome segregation by promoting the formation of functional kinetochore fibers, the microtubule bundles that align and segregate the chromosomes. Thus, actin is essential to prevent chromosome segregation errors in eggs, which are a leading cause of miscarriages, infertility, and Down syndrome.

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