Infertility: A missing motor protein causes the instability in human egg' s chromosomes

Miscarriages and infertility are common when human eggs have the improper amount of chromosomes. Human eggs are missing a crucial protein that works as a molecular motor, according to a study team led by Melina Schuh at the Max Planck Institute (MPI) for Multidisciplinary Sciences. During cell division, this motor aids in the stabilization of the machinery that splits the chromosomes. The findings open up new treatment avenues for reducing chromosomal segregation abnormalities in human eggs.

When a sperm fertilizes an egg, a new life begins. The genetic information from both parents is merged in this fusion. Each of the 23 chromosomes in the sperm and egg contributes a single copy. As a result, the newly developing embryo receives a full set of 46 chromosomes. However, because the oocyte (the egg's precursor cell) has two copies of each chromosome, it must lose half of them before fertilizations can occur. This occurs during meiosis, a type of cell division. The spindle apparatus is a complicated system that guarantees that a maturing egg preserves the correct number of chromosomes. During meiosis, it is made up of spindle fibers that adhere to the chromosomes. The fibers then drag one copy of each chromosome to the opposite poles of the spindle, causing the oocyte to divide.

In humans, this technique is prone to errors. There is a danger of miscarriage or disorders in the baby if too many or too few chromosomes remain in the mature egg, such as Down syndrome. "Human oocytes typically form spindles with unstable poles, as we already know. During division, such unstable spindles misarrange chromosomes "Melina Schuh, head of the MPI for Multidisciplinary Sciences' Department of Meiosis, agrees. In the animal realm, these high mistake rates are substantially lower. "In our trials, the spindles of other mammalian oocytes were always steady," she says.

Spindles that are unstable due to a lack of a motor protein

The researchers analyzed the molecular inventory of proteins essential for spindle stability in different mammalian oocytes to figure out what makes human spindles so fragile. Patients from the Bourn Hall Clinic (UK), Kinderwunschzentrum Göttingen (Germany), and Fertility Center Berlin (Germany) supplied unfertilized human oocytes that were immature at the time of fertility treatment for these tests. They used oocytes from mice, pigs, and cattle to compare to other mammalian species.

The protein KIFC1 is missing in human oocytes, according to the researchers. This motor protein helps to orient spindle fibres and keep them from falling apart by forming bridges between them. "Oocytes from mice, pigs, and cattle contain considerably more KIFC1 protein than human oocytes," says Chun So, a postdoctoral fellow in Schuh's department and the study's first author. The researchers then looked into how changing the protein amount influences spindle stability. They used Trim-Away, a new method co-developed in Schuh's lab, to deplete KIFC1 protein in mouse and bovine oocytes. Almost any target protein in any type of cell is rapidly degraded with this approach.

"Most mouse and bovine oocytes built unstable spindles like human oocytes without this motor protein, resulting in greater chromosomal segregation abnormalities. As a result, our findings show that KIFC1 is important for guaranteeing error-free chromosomal distribution during meiosis "adds the early-career researcher.

New therapeutic approaches rely on it as a foundation.

Could KIFC1 serve as a starting point for minimizing human egg chromosomal separation errors? "The intriguing question for us was whether additional KIFC1 in human oocytes makes spindles more stable." According to Schuh. Oocytes supplied with more KIFC1 showed much more stable spindles under the microscope, resulting in fewer chromosomal segregation mistakes. "Injecting KIFC1 into human oocytes could potentially be a way to lower the number of damaged eggs. This could aid in the success of fertility treatments "Max Planck's director has high hopes.

Reference:

Chun So, Katerina Menelaou, Julia Uraji, Katarina Harasimov, Anna M. Steyer, K. Bianka Seres, Jonas Bucevičius, Gražvydas Lukinavičius, Wiebke Möbius, Claus Sibold, Andreas Tandler-Schneider, Heike Eckel, Rüdiger Moltrecht, Martyn Blayney, Kay Elder, Melina Schuh. Mechanism of spindle pole organization and instability in human oocytes. Science, 2022; 375 (6581) DOI: 10.1126/science.abj3944