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CHROMOOCYTE Report Summary

Project ID: 337415
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - CHROMOOCYTE (Mechanisms of chromosome segregation in mammalian oocytes)

Human life starts with the fertilization of an egg. An egg and a sperm fuse and together they form a new genetically unique embryo. But surprisingly, human eggs frequently contain an incorrect number of chromosomes. Depending on the age of the woman, 10-50% of eggs are chromosomally abnormal. This high percentage of abnormal eggs results from chromosome segregation errors during oocyte maturation, the process by which an oocyte matures into a fertilisable egg. Thus, errors during meiosis in human oocytes are the most common cause of pregnancy losses and contribute to approximately 95% of human aneuploidy such as Down’s syndrome. Surprisingly, we still know very little about how mammalian oocytes mature into eggs, and it is still unclear why chromosome segregation during meiosis is so much more error-prone than during mitosis.
In the ChromOocyte project we are combining three innovative and complementary approaches towards understanding how homologous chromosomes are segregated and why oocyte maturation in mammals is so error-prone. Specifically, we are working towards the following three objectives:

1. Complete the first large scale screen for genes required for accurate progression through meiosis in mammalian oocytes and characterize the function of a few selected genes in detail.
2. Analyse meiosis and investigate potential causes of chromosome segregation errors directly in live human oocytes.
3. Study the function of an F-actin spindle and a chromosome-associated myosin that might be required for chromosome segregation in mammalian oocytes.

During the first half of this project, we have been able to complete the first large scale screen for genes required for accurate progression through meiosis (Pfender et al., Nature 2015). We have also made good progress towards the in depth functional analysis of genes that were identified in the screen. In particular, we have studied the function of Dusp7, a new phosphatase required for release
from prophase arrest (Tischer and Schuh, Cell Reports 2016, in press), as well as Btg4, a new protein required for MII arrest (Pasternak et al, Open Biology 2016). In addition, we have studied how genes that were identified as hits in the screen are involved in preventing polyspermy in mammalian oocytes (Cheeseman et al, Nature Communications 2016, in press).

Our lab has also pioneered methods that facilitated the first studies of meiosis and causes of aneuploidy directly in live human oocytes. We have been able to record videos of spindle assembly and chromosome segregation in more than 100 human oocytes. These videos allowed us for the first time to establish the different stages through which meiosis progresses in human oocytes. They also provided exciting new insights into the causes of chromosome segregation errors in human oocytes. We found that human oocytes often assemble a bipolar spindle by progressing through a prolonged multipolar spindle stage. Oocytes progressing through this stage are particularly likely to have lagging chromosomes in anaphase, a phenomenon that may be facilitated by a large number of abnormal kinetochore microtubule attachments in human oocytes. Thus, our data suggest that spindle instability and transient multipolarity contribute to the high frequency of chromosome segregation errors in human oocytes, even in young women (Holubcova et al., Science 2015).

Our work also shed light on why aneuploidy in human oocytes increases with maternal age. We found that many sister kinetochores in human oocytes are separated and do not behave as a single functional unit during the first meiotic division. Having separated sister kinetochores allows bivalents, the unit of two homologous chromosomes linked to each other by recombination, to rotate by 90 degrees on the spindle and increased the risk of merotelic kinetochore-microtubule attachments. Advanced maternal age led to an increase in sister kinetochore separation, rotated bivalents and merotelic attachments. Chromosome arm cohesion was weakened, and the fraction of bivalents that precociously dissociated into univalents was increased. Together, these data suggest that multiple age-related changes in chromosome architecture contribute to the increase of oocyte aneuploidy with advanced maternal age (Zielinska et al., Elife 2015).

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