Cell News 04/2018
11
NIKON YOUNG SCIENTIST AWARD 2018
nism behind chromosome mis-segregation in women. However
historically, human eggs have been largely inaccessible to
research. This is because the oocyte pool is buried deep within
the abdominal cavity and while an egg is ovulated each men-
strual cycle, it cannot be captured and retrieved easily. There-
fore, our understanding of how chromosome mis-segregate in
mammalian eggs comes predominantly from studies in mice.
A few pivotal studies demonstrated that in mice, ageing induc-
es global age-related changes in chromosome organization:
the oocyte’s chromosomes have been shown to progressively
uncouple as the mouse gets older
6-8
. This is because some of
the proteins in oocytes are long-lived with low renewal rates.
As a result, the chromosome-associated pool of these proteins
declines as the female gets older and their abundance may
become insufficient to confer the desired function. In particu-
lar, several studies have demonstrated that cohesin complexes,
which hold chromosomes and chromatids together during both
meiotic divisions, are particularly long lived
9
.
The two homologous chromosomes have to remain tight-
ly linked throughout meiosis I, so that they only partition
at anaphase I onset and their separation occurs in a highly
synchronized and well co-ordinated manner
2
. The meiosis I
homologous chromosome complex is called a bivalent chro-
mosome and indeed cohesin complexes maintain the bivalent
structure via two means: firstly, by keeping the two homol-
ogous chromosomes together in the arm regions
4
. Secondly,
by maintaining a tight association between sister chromatids
in their centromeric regions. As the aim of any cell division is
to equally partition the DNA between the two daughter cells,
the premature loss of bivalent integrity due to an age-related
cohesin loss can be detrimental to chromosome segregation
outcomes. If cohesins are lost and the homologous chromo-
somes of a bivalent separate prematurely, no longer are they
recognized by the spindle microtubules as a linked entity. As
a result, they interact with distinct microtubule bundles and
segregate in an unsychronised manner, which frequently leads
to chromosome segregation errors.
As cohesin complexes are present both along chromosome
arms and between sister kinetochores, a reduction in centro-
meric cohesion could also affect sister kinetochore geometry.
Namely, because cohesins promote the high proximity of
sister chromatids, cohesion loss should increase the spacing
between sister kinetochores. This prediction has indeed been
verified in mouse oocytes using microscopy approaches. Sister
kinetochores were demonstrated to become easier to resolve
by microscopy techniques as the mouse gets older and cohes-
ins become lost
10
. However, while the premature separation
of homologous chromosomes has been unequivocally linked
to chromosome segregation errors in ageing female mice, the
slight increase in sister kinetochore spacing only marginally
affected kinetochore-microtubule interactions
11
.
Whether similar age-related changes occur in women and
how ageing influences the chromosome architecture in human
oocytes remained however largely unclear. Because genetic
studies demonstrated that aneuploidy in human oocytes largely
exceeds that observed in mice, this further suggested that
additional mechanisms may play a role in the striking rate of
aneuploidy characteristic of humans. Altogether, it became
evident that new experimental approaches are necessary to
elucidate the mechanisms behind the unexpected rate of errors
in human eggs.
Illuminating meiotic processes directly in
human eggs
To breach this gap, our lab recently established an experimen-
tal setup to study meiosis directly in live and fixed human
oocytes
12-14
. To achieve this, we utilized the fact that an in-
creasing number of women worldwide has to resort to Assisted
Reproductive Treatments (ART) in order to conceive. ART entails
harvesting around a dozen oocytes and subsequently iden-
tifying the best quality cells for subsequent fertilization. We
reasoned that a surplus oocytes from fertility treatments could
be utilized, following an informed patient’s consent, to eluci-
date the mechanistic basis of chromosome mis-segregation in
humans. By collaborating with the world’s first fertility centre
Bourn Hall, established by Nobel Prize Laureates Bob Edwards
and Patrick Steptoe, I was in the privileged position to address
the pressing questions in developmental biology directly in hu-
man eggs. Namely, what aspects of the chromosome segrega-
tion machinery make human female gametes particularly prone
to errors. Therefore, we set out to establish the first detailed
screen of how oocyte’s chromosome architecture changes as
the woman gets older
13
.
Mechanism I: human meiotic kinetochores are
not fully unified and the degree of kinetochore
separation increases with advancing maternal age
At the onset of our study, it was generally believed that
meiotic kinetochores remain tightly linked throughout the
first division of the oocyte
13
. This tight linkage of sisters would
allow the two sister kinetochores to act as one functional unit
and interact with a single spindle pole only. This unification of
sister kinetochores would therefore aid the special task of sep-
arating whole chromosomes and not sister chromatids during
the first division of the oocyte, a task that is unique to meiosis
I. Indeed, this was confirmed in mouse oocytes, where each
sister kinetochore pair was shown to reliably attach to only one
spindle pole.
Using advanced microscopy techniques to visualize fluores-
cently labelled chromosomes and kinetochores and subsequent
in-depth analysis of chromosome architecture in 3D space
14
,
I was able to demonstrate that human oocytes challenge this
dogma of meiosis
13
. Our analysis revealed that incongruently
with predictions based on model organisms, kinetochores even
in oocytes from women in their early twenties are frequently
not physically fused (Figure 2). This was in contrast to kine-
tochores in young mice, which due to their high proximity
