Fishing games gone wrong: Trial-and-error behind important cause of female infertility

When an egg cell is being formed, the cellular machinery which separates chromosomes is extremely imprecise at fishing them out of the cell's interior, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have discovered.

The unexpected degree of trial-and-error involved in this process could explain why errors in the number of chromosomes in the egg cell are the leading cause of miscarriages and severe congenital diseases such as trisomies like Down's syndrome, as well as an important cause of female infertility.

he findings are published online in Cell.

Our cells have two copies of each chromosome, one inherited from our mother and the other from our father. An oocyte, the cell that matures into an egg cell, has to discard half of its chromosomes, keeping only the maternal or paternal copy of each. To do so, fibres called microtubules act like fishing lines, attaching themselves to chromosomes and reeling them in to opposite sides of the cell. However, the EMBL scientists discovered that these microtubules are much worse fishermen than expected, often incorrectly hooking onto a chromosome and having to let it go again.

"We saw that they have to go through several tries before getting the connection right," says Jan Ellenberg, who led the work at EMBL: "overall, 90% of all chromosomes get connected in the wrong way, and therefore the pathway that corrects these errors is heavily used."

The difficulty in the oocyte is that two fishing lines cast from opposite sides of the cell have to attach themselves to the maternal and paternal copies of the same chromosome. Each of those chromosome copies has a protein structure called a kinetochore, which acts like the magnet in a toy fish, providing the spot for the microtubule 'fishing lines' to attach themselves. The EMBL scientists were the first to track the movement of all kinetochores throughout the whole 8 hours of the first round of cell division in mouse egg cells, which are very similar to human ones.

"We were able to get very high resolution images for extended periods of time," explains Tomoya Kitajima, who carried out the work, "because our lab developed a microscope that automatically searches for chromosomes, zooms in, and scans only the area they are in, doing very little damage to the cell."