Women’s fertility starts to decline significantly at around the age of 35. Now, researchers at the University of Montreal Hospital Research Center (CRCHUM) have discovered a possible new explanation for this phenomenon.
Using cutting-edge microscopy techniques, the researchers at CRCHUM observed, for the first time, a specific defect in the eggs of older mice:
The choreography of cell division goes awry and causes errors in the sharing of chromosomes.
In other words, age-related female infertility in mice is explained by a defect in some of the specific steps involved in chromosome segregation during cell division in eggs before they are fertilized. The researchers say this defect may also be found in the eggs of older women.
Here is what it looks like (Video courtesy of Greg FitzHarris laboratory, CRCHUM. The chromosome segregation in mouse eggs. The spindle is labeled in green, and the chromosomes are labeled in red.):
Instead of following the normal orderly process of segregating chromosomes to distribute to daughter cells during cell division, segregation in older eggs is flawed leading to abnormal numbers of chromosomes, a state known as aneuploidy. There can be too many chromosomes or too few.
Aneuploidy increases with age. It is believed that these defective eggs are a key reason to why older women have trouble getting pregnant and having full-term pregnancies. It is also known that they increase the risk of miscarriage and can cause Down’s syndrome in full-term babies.
The cause of the abnormal chromosomal segregation is related to tiny cylindrical structures in the cells called microtubules. Their function is to organize into a spindle that gathers the chromosomes together and sorts them at the time of cell division. The chromosomes are then sent to the opposite poles of the daughter cells.
According to FitzHarris, their observations in mice showed that
“approximately 50% of the eggs of older females have a spindle with chaotic microtubule dynamics. Instead of assembling a spindle in a controlled symmetrical fashion, the microtubules go in all directions. The altered movement of the microtubules apparently contributes to errors in chromosome segregation, and so represents a new explanation for age-related infertility.”
These unprecedented observations were being published April 3, 2017 in Current Biology in an article titled “Intrinsically defective microtubule dynamics contribute to age-related chromosome segregation errors in mouse oocyte meiosis-I.”
Making sense of the findings
Scientists previously believed that eggs are more likely to be aneuploid with age because the “glue” that keeps the chromosomes together works poorly in older eggs. This is known as the “cohesion-loss” hypothesis.
Professor FitzHarris doesn’t think that their current observations contradict that hypothesis, rather, he says, it “shows the existence of another problem: defects in the microtubules, which cause defective spindles and, in doing so, seem to contribute to a specific type of chromosome segregation error.”
To further elucidate the role of maternal age, the researchers conducted a series of micromanipulations on the eggs of mice between the ages of 6 and 12 weeks (young) and 60-week-old mice (old). Shoma Nakagawa, a postdoctoral research fellow at the CRCHUM and at the Université de Montréal explains,
“We swapped the nuclei of the young eggs with those of the old eggs and we observed problems in the old eggs containing a young nucleus. This shows that maternal age influences the alignment of microtubules independently of the age of the chromosomes contained in the nuclei of each egg.”
Greg FitzHarris’s team notes that spindle defects are also a problem in humans. In short, the cellular machinery works less efficiently in aged eggs, but this is not caused by the age of the chromosomes.
Hope for the future
The hope is that this discovery may one day lead to new fertility treatments to help women become pregnant and carry a pregnancy to term. As FitzHarris explains,
“We are currently exploring possible treatments for eggs that might one day make it possible to reverse this problem and rejuvenate the eggs.”
According to the researchers, many more years of research will be needed before getting to that point. But understanding the precisely orchestrated choreography that unfolds within each egg during cell division will eventually allow us to correct the errors, to ensure the production of healthy eggs that can be fertilized.
About this study
This research initiative was funded by the Canadian Institutes of Health Research (MOP142334), the J.-Louis Lévesque Foundation and the Canada Foundation for Innovation (FCI32711). Greg FitzHarris is a researcher at the CRCHUM and a professor in the Department of Obstetrics and Gynecology at the Université de Montréal. Shoma Nakagawa is a postdoctoral research fellow at the CRCHUM and at the Université de Montréal. The full article is available Current Biology, 2017 DOI: 10.1016/j.cub.2017.02.025.