Why egg cells become error-prone with age

October 31, 2019
For women, the biological clock starts ticking by their mid-30s at the latest: Fertility decreases, the risk of miscarriages increases. One of the main reasons behind both are eggs with altered chromosome numbers. It has remained largely unclear, however, why eggs from older women more frequently possess too many or too few chromosomes. A German-English research team has now discovered that certain structures on the egg’s chromosomes age and fall apart, possibly promoting incorrect chromosome distribution. (Current Biology, October 31, 2019)

A new life begins when an egg is fertilized by a sperm. This is when the genetic information of the father and the mother is combined: Sperm and egg each contribute one copy of the 23 chromosomes that carry the genetic information (DNA), so that the newly formed embryo inherits a full set. However, the egg’s precursor cell contains two copies of each chromosome and, therefore, must eliminate half of its 46 chromosomes before fertilization. This happens in a specialized cell division process, called meiosis, during which the actual egg matures. The problem is that this process becomes increasingly error-prone as women get older. That is because a woman's immature eggs are already produced at birth: A 40-year-old woman has 40-year-old eggs. The older the woman and the egg get, the more likely it is that the mature egg has too many or too few chromosomes. This is one of the main causes behind miscarriage and human infertility.

A complex cellular machine, the spindle apparatus, ensures that a maturing egg retains the correct number of chromosomes. The spindle apparatus consists of spindle fibers that attach to the chromosomes during meiosis. Each fiber pulls one copy of each chromosome pair towards one of two opposite poles like a winch – the cell will divide between these poles. Importantly, the spindle fibers do not bind directly to the chromosome, but to a specialized structure, the so-called kinetochore. The kinetochore is anchored at the centromere, a special region of the chromosome. At the centromere, the chromosome’s DNA is packed particularly tightly.

“We have studied for quite some years now why the distribution of chromosomes in eggs becomes more error-prone with age,” reports Melina Schuh, Director at the MPI for Biophysical Chemistry, “and we have already found various factors in the egg that contribute to this. However, the picture is still incomplete.”

Together with her team and researchers at Bourn Hall Clinic in Cambridge (England), the cell biologist has now investigated the mature egg’s kinetochore for the first time. The unfertilized eggs for these studies came from Bourn Hall Clinic and the Kinderwunschzentrum Göttingen. Women had donated them anonymously for research – otherwise the eggs would have been discarded, as they were not sufficiently mature for in vitro fertilization. “The kinetochores play a central role in chromosome distribution: The spindle fibers pull on them for numerous hours as the chromosomes become sorted and arranged on the spindle. They are therefore exposed to very strong forces,” Schuh explains. “We wanted to know whether anything changes in or around this anchor point due to age.” Indeed, her team discovered that the centromere becomes less tightly packed in old eggs, and that a staggering one in three kinetochores had fallen apart.

Molecular signs of aging

But why do centromeres and kinetochores decompose as the female ages? A key player in this process seems to be a protein complex called cohesin. Cohesins are attached to certain areas of the chromosome like a tight rubber ring and stabilize them. “We already knew that the amount of cohesin at chromosomes decreases with age,” explains Agata Zielinska, a former PhD student in Schuh’s lab. When she artificially reduced the amount of cohesin in young eggs, she observed the same effects – loosened centromeres, decayed kinetochores – that the scientists had found in old eggs. “The age-related lack of cohesin apparently causes damage to centromeres and kinetochores in older eggs,” Zielinska summarizes. 

“We thus knew that a large fraction of kinetochores fragment in aging eggs. Next, we wanted to find out whether the disintegration of the kinetochores could be linked to incorrect chromosome distribution,” says Schuh. In further experiments, the researchers discovered that in about one third of cases, the individual parts of a fragmented kinetochore were simultaneously attached to spindle fibers of both poles. “In such cases it is no longer clear to which pole the spindle fibers pull the chromosomes during cell division,” Schuh continues, “and when the egg is ready to divide, distribution errors may arise that contribute to infertility and miscarriages.” (kl/fk)  

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