Sloppy fishing: why meiosis goes wrong
Submitted by brown on 07 November 2012
By Sonia Furtado Neves, EMBL
As an egg cell, or oocyte, matures inside a woman’s ovary, it undergoes a type of cell division called meiosis, in which the pairs of chromosomes inside it are lined up and fished apart, and half of them are expelled. The chromosomes are brought together from all over the cell (Mori et al., 2011) and fished apart by protein rods called microtubules. Like the child’s rod pulling a toy fish by its magnet, a microtubule catches a chromosome by its kinetochore – a cluster of protein and genetic material at the centre of the chromosome’s X shape.
The main events of human meiosis during egg cell maturation. Click on image to enlarge.
A: During the first five months of development of a female human embryo, all its potential future egg cells are formed. In each of these cells, after DNA duplication, homologous chromosomes exchange genetic material during crossing over. Meiosis is then halted until ovulation, and most of the potential egg cells die off again.
B: Between puberty and menopause, during each monthly cycle, a few potential egg cells progress further during the stages of meiosis, but only one at a time eventually completes the process. Homologous chromosomes line up at the primary egg cell’s equator and are then fished apart by microtubules. The primary egg cell divides into a secondary egg cell and a polar body.
Now paired chromatids line up at the equators of both the polar body and the egg cell, and at the time of ovulation, microtubules attach to them. Meiosis is arrested here until fertilisation.
C: If fertilisation happens, the paired chromatids are pulled apart, moving to opposite poles of the cells. The polar body divides in two, the secondary egg cell divides into a third polar body and a mature egg cell, and meiosis is complete. Each of the four resulting daughter cells has a different genetic makeup.
The genetic material of the polar bodies is discarded, while that of the mature egg cell is joined by the genetic material of the fertilising sperm, to start the development of a new embryo. Click on image to enlarge.
Image courtesy of Nicola Graf
By examining mouse egg cells under the microscope, EMBL scientist Tomoya (Tomo) Kitajima was the first to track the movements of all of an egg cell’s kinetochores during the whole of cell division – all 10 hours of it. “We were able, for the first time, to keep track of all the kinetochores throughout cell division – so there’s not a single time point where it’s ambiguous where that part of the chromosome is – and that’s really a breakthrough in the field, achieving this in these very large and light-sensitive cells,” says Jan Ellenberg, who heads the research group.
By focusing the microscope only on the part of the cell where the chromosomes are, Tomo was able to obtain high-resolution images at short intervals of only one and a half minutes, which gave him a very clear picture of the process. And, because the microscope was only firing light at that small region of the oocyte, it did less damage to the cell, which enabled the scientists to keep up the imaging for the 10 hours of cell division (see box for more on smart microscopy).
“But even with this pre-positioning, it still doesn’t work very well,” says Jan. “We saw that 90 % of kinetochore connections were initially wrongly established, and the microtubules had to release the chromosome and try again – on average, this had to be done three times per chromosome.”
During mitosis, the microtubule rods start forming at two opposite points in the cell and come together in a lemon-shaped structure – the spindle – that then pulls each chromatid in a pair to one side, or pole. But in meiosis, as Jan’s group discovered a few years ago (Schuh & Ellenberg, 2007), the spindle’s microtubules converge from as many as 80 different points at first, and only later arrange themselves into a two-poled structure. “So when microtubules are first attaching to chromosomes, it’s hard to know if they’re going to end up pulling them in opposite directions or not,” Jan explains. This, along with the fact that the egg cell is a much larger expanse across which microtubules have to find and drag chromosomes – a human egg cell is more than four times larger than a skin cell – could explain why chromosome fishing is so much more error-prone in egg-cell division.
Making microscopes smarter
The software that Tomo used to find and film chromosomes throughout cell division was a prelude of things to come. Since then, in collaboration with another team at EMBL led by Rainer Pepperkok, Jan’s group has developed a more complex programme, capable of even greater feats of automation. Called Micropilot, the new software analyses low-resolution images taken by a microscope and finds not just chromosomes but whatever structure the scientist has taught it to look for.
More about EMBL
EMBL is a member of EIROforumw2, the publisher of Science in School.
Kitajima TS, Ohsugi M, Ellenberg J (2011) Complete kinetochore tracking reveals error-prone homologous chromosome biorientation in mammalian oocytes. Cell 146(4): 568-81. doi: 10.1016/j.cell.2011.07.031
Magidson V et al. (2011) The spatial arrangement of chromosomes during prometaphase facilitates spindle assembly. Cell 146(4): 555-67. doi: 10.1016/j.cell.2011.07.012
Mori M et al. (2011) Intracellular transport by an anchored homogeneously contracting F-actin meshwork. Current Biology 21: 606-61. doi: 10.1016/j.cub.2011.03.002
Schuh M, Ellenberg J (2007) Self-organization of MTOCs replaces centrosome function during acentrosomal spindle assembly in live mouse oocytes. Cell 130(3): 484-98. doi: 10.1016/j.cell.2007.06.025
w1 – For more information about EMBL, see the EMBL website.
w2 – EIROforum is a collaboration between eight of Europe’s largest inter-governmental scientific research organisations, which combine their resources, facilities and expertise to support European science in reaching its full potential. As part of its education and outreach activities, EIROforum publishes Science in School.
Watch a video of microtubules nudging the chromosomes into position.
If you found this article interesting, why not browse the other cutting-edge research articles in Science in School?
Sonia Furtado Neves was born in London, UK, and moved to Portugal at the age of three. While studying for a degree in zoology at the University of Lisbon, she worked at Lisbon Zoo’s education department; there, she discovered that what she really enjoys is telling people about science. She went on to do a master’s degree in science communication at Imperial College London, and is now the press officer at the European Molecular Biology Laboratory in Heidelberg, Germany.
This article is about new scientific inputs concerning the understanding of cell division mechanisms, namely the attachment of microtubules to chromosomes during mitosis and meiosis.
The level of detail in this article makes it particularly useful for upper-secondary biology classes (ages 15+), for topics such as cytology (mitosis and meiosis), genetics (the causes and implications of chromosomal abnormalities) and reproduction (gametogenesis and infertility).
The article can also be used to initiate wider discussions about both the benefits of modelling biological phenomena (models can help us to understand processes) and the risks. For example, in the majority of text-books describing mitosis and meiosis, chromosomes are represented as large structures. This can lead students to believe that chromosomes are easily observable in any type of cells. As is clear from the article, however, this is not the case.
Finally, the article illustrates how the efforts made in one research group might benefit other research areas, as well as highlighting the synergistic relationship between science and technology.
Betina da Silva Lopes, Portugal