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Why female fertility declines with age

Female infertility in aging mothers may be due to a defect in chromosome sharing during cell division — before eggs are fertilized. Women's eggs lie dormant in ovaries until release of one egg per menstrual cycle. But, fertility declines significantly in women around the age of 35.

Thanks to cutting-edge microscope techniques, researchers at the University of Montreal Hospital Research Center (CRCHUM) found a possible new explanation for female infertility. They observed a specific defect in eggs of older mice — one which may also be found in the eggs of older women. When the choreography of cell division goes wrong, it causes errors in the sharing of chromosomes. Their observations are published in Current Biology.

"We found that microtubules which orchestrate chromosome segregation during cell division behave abnormally in older eggs. Instead of assembling a spindle in a controlled symmetrical fashion, they go in all directions. This altered movement contributes to errors in chromosome segregation, and represents a new explanation for age-related infertility."

Greg FitzHarris PhD, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM); Professor, Department of Obstetrics and Gynaecology, University of Montréal, Montreal, Canada.

Microtubules are tiny cylindrical structures that organize themselves to form a spindle. The spindle gathers chromosomes together and — at cell division — sorts them through chromosome segregation, sending chromosomes to the opposite poles of a dividing cell.

Conducting a series of micromanipulations on eggs from mice between the ages of 6 and 12 weeks (young) and 60-weeks (old): "When we swapped the nuclei of the young eggs with those of old eggs, we observed problems in old eggs containing a young nucleus. This shows that maternal age influences the alignment of microtubules independent of age of chromosomes contained in the nuclei of each egg," explains Shoma Nakagawa, a postdoctoral research fellow at CRCHUM and the Université de Montréal.

"One of the main causes of female infertility is a defect in eggs that causes them to have an abnormal number of chromosomes. These so-called aneuploid eggs become increasingly prevalent as women age."

Greg FitzHarris PhD

FitzHarris's team points out that less efficientl cellular machinery in aged eggs is not caused by the age of the chromosomes. Science previously believed older eggs are more likely to be aneuploid due to "glue" not keeping chromosomes together over time. This is known as the "cohesion-loss" hypothesis. "Our work doesn't contradict that idea, but shows existence of another problem: defects in the microtubules, which cause defective spindles to contribute to a specific type of chromosome segregation error" adds FitzHarris.

"In mice, approximately 50% of the eggs of older females have a spindle with chaotic dynamics"

Greg FitzHarris PhD

The discovery may one day lead to new fertility treatments to help women become pregnant and carry a pregnancy to term. "We are currently exploring possible treatments ... to reverse this problem and rejuvenate the eggs," explains FitzHarris. Many more years of research will be needed before getting to this point.

•Microtubule dynamics is altered in oocytes from naturally aged mice
•Multipolar spindles precede missegregation of intact sister chromatid pairs
•Chromosome swapping reveals spindle defects are not attributable to chromosome aging

Chromosome segregation errors in mammalian oocytes compromise development and are particularly prevalent in older females, but the aging-related cellular changes that promote segregation errors remain unclear [ 1, 2 ]. Aging causes a loss of meiotic chromosome cohesion, which can explain premature disjunction of sister chromatids [ 3–7 ], but why intact sister pairs should missegregate in meiosis-I (termed non-disjunction) remains unknown. Here, we show that oocytes from naturally aged mice exhibit substantially altered spindle microtubule dynamics, resulting in transiently multipolar spindles that predispose the oocytes to kinetochore-microtubule attachment defects and missegregation of intact sister chromatid pairs. Using classical micromanipulation approaches, including reciprocally transferring nuclei between young and aged oocytes, we show that altered microtubule dynamics are not attributable to age-related chromatin changes. We therefore report that altered microtubule dynamics is a novel primary lesion contributing to age-related oocyte segregation errors. We propose that, whereas cohesion loss can explain premature sister separation, classical non-disjunction is instead explained by altered microtubule dynamics, leading to aberrant spindle assembly.

The article: Intrinsically defective microtubule dynamics contribute to age-related chromosome segregation errors in mouse oocyte meiosis-I was published on April 3, 2017 in Current Biology. 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. DOI: 10.1016/j.cub.2017.02.025.

Related articles
Gene mutation may explain female infertility
Male infertility may be due to failure of calcium signal
How eggs get the wrong number of chromosomes
Cell division errors: infertility, disorders and cancers

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Chromosome segregation in mouse eggs

Image Credit: Greg FitzHarris laboratory, CRCHUM


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