Fertility: A missing 'motor' causes our eggs to fail
Mechanism of spindle pole organization and instability in human oocytes


Date:
February 14, 2022
Source:
Max-Planck-Gesellschaft
Summary:
Human eggs often contain the wrong number of chromosomes, leading
to miscarriages and infertility. A research team has discovered
that human eggs are missing an important protein, which acts as
a molecular motor.

This motor helps to stabilize the machinery that separates the
chromosomes during cell division. The researchers' findings open up
new avenues for therapeutic approaches that could reduce chromosome
segregation errors in human eggs. Researchers essentially find a
way to recapitulate spindle stability in human eggs.



FULL STORY ========================================================================== Human eggs often contain the wrong number of chromosomes, leading to miscarriages and infertility. A research team led by Melina Schuh at
the Max Planck Institute (MPI) for Multidisciplinary Sciences has
discovered that human eggs are missing an important protein, which
acts as a molecular motor. This motor helps to stabilize the machinery
that separates the chromosomes during cell division. The researchers'
findings open up new avenues for therapeutic approaches that could reduce chromosome segregation errors in human eggs.


==========================================================================
A new life begins when an egg is fertilized by a sperm. In this fusion,
the genetic information from each parent is combined. The sperm and egg
both contribute a single copy of each of their 23 chromosomes. The newly developing embryo thus inherits a complete set of 46 chromosomes. However,
the oocyte - - the egg's precursor cell -- contains two copies of every chromosome and must therefore lose half of these before fertilization
can take place. This happens in a specialized cell division called
meiosis. A complex machinery -- the spindle apparatus -- ensures that a maturing oocyte retains the correct number of chromosomes. It consists of spindle fibers that attach to the chromosomes during meiosis. The fibers
then pull one copy of each chromosome to opposite poles of the spindle,
and the oocyte subsequently divides between them.

This process is highly error-prone in humans. If too many or too few chromosomes remain in the mature egg, there is a risk of miscarriage
or diseases in the offspring such as Down syndrome. "We already
know that human oocytes frequently assemble spindles with unstable
poles. Such unstable spindles misarrange chromosomes during division,"
says Melina Schuh, who heads the Department of Meiosis at the MPI
for Multidisciplinary Sciences. These high error rates are much lower
elsewhere in the animal kingdom. "The spindles of other mammalian oocytes
were always stable in our experiments," she reports.

Unstable spindles due to a missing motor protein To find out what makes
human spindles so unstable, the team compared the molecular inventory
of proteins required for spindle stability, in different mammalian
oocytes. For these experiments, the researchers used unfertilized human
oocytes that were immature at the time of fertility treatment and donated
by patients of the Bourn Hall Clinic (UK), Kinderwunschzentrum Go"ttingen (Germany) and Fertility Center Berlin (Germany) for research. For
comparison with other mammalian species, they used oocytes from mice,
pigs, and cattle.

The researchers discovered that human oocytes are deficient in the protein KIFC1. This motor protein forms bridges between spindle fibers, which
help to align the fibers and prevent them from falling apart. "Compared
to humans, oocytes from mice, pigs, and cattle contain significantly
more KIFC1 protein," explains Chun So, a postdoctoral fellow in Schuh's department and the first author of the study. The scientists next
investigated whether manipulation of the protein level affects spindle stability. They depleted KIFC1 protein in mouse and bovine oocytes using
a new method co-developed in Schuh's lab called Trim-Away. This technique rapidly degrades almost any target protein in any type of cell. "Without
this motor protein, most mouse and bovine oocytes assembled unstable
spindles like human oocytes and more chromosome segregation errors
occurred. Thus, our results suggest that KIFC1 is critical in ensuring error-free distribution of chromosomes during meiosis," the early career researcher adds.

A cornerstone for new therapeutic approaches Could KIFC1 be a starting
point for reducing chromosome separation errors in human eggs? "For us,
the exciting question was: Do spindles become more stable if we introduce
extra KIFC1 into human oocytes?" Schuh says. Indeed, under the microscope, oocytes supplemented with extra KIFC1 had significantly more stable
spindles, resulting in fewer chromosome segregation errors. "Introducing
KIFC1 into human oocytes could thus be a possible approach to reduce
defective eggs.

This might help to make fertility treatments more successful," the Max
Planck director hopes.

========================================================================== Story Source: Materials provided by Max-Planck-Gesellschaft. Note:
Content may be edited for style and length.


========================================================================== Related Multimedia:
* Meiosis ========================================================================== Journal Reference:
1. Chun So, Katerina Menelaou, Julia Uraji, Katarina Harasimov, Anna M.

Steyer, K. Bianka Seres, Jonas Bucevičius, Gražvydas
Lukinavičius, Wiebke Mo"bius, Claus Sibold, Andreas Tandler-
Schneider, Heike Eckel, Ru"diger 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220214095811.htm

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