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beginning of life

Double trouble at the
beginning of life

By Agata P. Zielinska and Melina Schuh
Every human life begins with the fertilization
of an egg (1). Once the egg
and the sperm have fused, the parental
chromosomes need to be united.
To this end, the egg and sperm chromosomes
are first packaged into two
separate membrane-enclosed nuclei. These
nuclei then slowly move toward each other
and break down in the center of the fertilized
egg, called the zygote. Only then are
the maternal and paternal chromosomes
united—but not quite. Surprisingly, the parental
chromosomes do not mix immediately
but instead occupy distinct territories in
the zygote throughout the first cellular division
(2, 3). How the autonomy of parental
genomes is retained after fertilization has
remained unclear. On page 189 of this issue,
Reichmann et al. (4) used elegant microscopy
methods to illuminate this special moment,
when the parental chromosomes first meet in
live mouse zygotes, and follow how the chromosomes
become distributed as the zygote
divides. Their findings reveal an unexpected
mechanism that keeps the parental genomes
apart during the first division of the embryo:
The male and female chromosomes each assemble
their own chromosome separation
machineries. This increases the probability
that chromosomes are separated into multiple,
unequal groups, which may compromise
embryo development and give rise to spontaneous
miscarriage.
Reichmann et al. labeled the maternal
and paternal chromosomes in different
colors by taking advantage of distinct DNA
sequences (5 ) in the parental chromosomes,
which came from different mouse strains
(6). To follow in detail how the chromosomes
are united, zygotes have to be imaged
at very high spatial and temporal resolution.
However, embryos are light sensitive,
which has hindered a detailed analysis in
the past. The authors overcame this limitation
by using an innovative light-sheet
microscope, which illuminates the embryo
selectively in the region of interest but not
in adjacent regions, as is the case with standard
microscopy approaches (7). This reduces
the amount of light that the embryo
is exposed to. Moreover, this method is fast
and allowed the authors to reconstruct the
entire volume that is occupied by the chromosomes
with unprecedented spatial and
temporal resolution.
The authors tracked the maternal and
paternal chromosomes as they first met. In
addition, they imaged microtubules, the proteinaceous
fibers that form the spindle apparatus
that captures, aligns, and distributes
the chromosomes equally between the two
daughter cells of the dividing zygote. Surprisingly,
Reichmann et al. found that the maternal
and paternal chromosome masses each
assemble a separate spindle structure that
autonomously initiates chromosome alignment
(see the images). Later, the two spindles
merge into a single spindle. However, the maternal
and paternal chromosomes remain in
separate regions of the merged spindle and
do not mix.
Max Planck Institute for Biophysical Chemistry, Göttingen
37077, Germany. Email: melina.schuh@mpibpc.mpg.de
128 13 JULY 2018 • VOL 361 ISSUE 6398
EMBRYOGENESIS
Double trouble at the
beginning of life
Dual-spindle assembly in early embryos can
compromise mammalian development
Published by AAAS
Downloaded from http://science.sciencemag.org/ on August 6, 2018
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Whether the spatial separation of parental
chromosomes has any advantages for the
developing mammalian embryo is unclear.
However, the fact that zygotes have a dual
spindle creates a previously unforeseen
source of potential error. The final task the
zygote has to accomplish before it divides
is to align the two spindle axes in parallel
to each other, so that the two spindles can
merge into a compact dual structure. If the
poles of the spindles fail to align and merge,
the genetic material of the zygote could be
pulled into three or four directions
instead of two (see the
figure). Reichmann et al. demonstrate
that spindle misalignment
leads to the formation of
multinucleated embryos that
have more than one nucleus per
cell. It is easy to envision that
such an undesired partitioning
of the DNA would have a
negative impact on the fidelity
of subsequent cell divisions
and hence might compromise
embryo development. Indeed,
experience from in vitro fertilization
(IVF) clinics shows that
early human embryos cultured
in vitro before implantation frequently
have multiple nuclei in
their cells (8) and then fail to
develop further (9).
To evaluate the implications of
these findings for human infertility,
it is important to investigate
whether cells with multiple nuclei
in human embryos are also
caused by defects during dualspindle
merging, as reported for
mouse embryos in this study. In
humans, the sperm delivers a
centrosome into the zygote (10,
11). Centrosomes are microtubule-
organizing centers that help
to generate a bipolar spindle in
somatic cells (12). However, in
mice, the sperm does not carry
a centrosome, and the zygotic
spindle needs to assemble without
the help of centrosomes (1).
Reichmann et al. demonstrate
that chromosomes play a key
role in driving spindle assembly
in the mouse zygote. The chromosome-
based spindle assembly
mechanism seems to create a
permissive environment for the formation of
two independent spindle structures.
The presence of centrosomes in human zygotes
could facilitate the assembly of a single
bipolar spindle. However, it is still unclear
whether spindle assembly in human zygotes
is primarily centrosome driven, or whether
they also assemble two distinct spindles from
chromosome surfaces. Interestingly, spindle
assembly in unfertilized human eggs is
largely chromosome driven (13), which raises
the possibility that also in human zygotes,
even in the presence of centrosomes, chromosome-
driven spindle assembly may occur.
In many countries, the law considers that
new human life begins when parental chromosomes
are united upon fertilization (14).
This work is a reminder that the definition
of the unification of parental genomes as the
beginning of life is not as clear cut as was previously
assumed. How we define the “beginning
of life” not only has ethical implications
but also practical repercussions for fertility
treatments. This is because in some countries,
such as Germany (14), parental nuclei are allowed
to merge and hence life is allowed to
“begin” in IVF clinics only in a very limited
number of in vitro–cultured zygotes, all of
which have to be transferred to the mother.
This policy increases the rate of multiparous
pregnancies, which are associated with severe
risks to the health of the mother and her
children. Additionally, because identification
of the most promising fertilized eggs has to
legally occur before the parental genomes
have merged (so that embryos with merged
genomes, defined as being human life, are
not discarded), embryologists have to select
embryos for implantation at the
zygotic stage. Because our understanding
of early human embryogenesis
is still poor, it is difficult
to select at this early stage the
embryos that have the highest
chance of dividing correctly,
implanting, and giving rise to a
healthy pregnancy. Considering
that there is now comprehensive
evidence that the parental DNA
does not mix in live zygotes, this
study highlights that a dialogue
is needed to reshape the legal
definition of when life begins, so
that it is supported by up-to-date
scientific knowledge. By revisiting
this definition, we could increase
the chances of a healthy
pregnancy among couples who
otherwise struggle to conceive. j
First mitosis in mammals
Two-cell
embryo
First
mitotic
anaphase
Mature
frst
mitotic
spindle
Early stages
of spindle
assembly
Nuclear
envelope
breakdown
Zygote
Polar body
Sperm
Mitotic spindle
Paternal chromosomes
Maternal
chromosomes
Formation
of two
nuclei
Fertilization
Old model
Correct axis
alignment
One nucleus
per cell
Multinucleated
cells
Incorrect axis
alignment
Current model
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    10.1126/science.aau3216
    13 JULY 2018 • VOL 361 ISSUE 6398 129
    Immunofluorescence staining of a mouse zygote
    (left image) shows parallel alignment of two mitotic
    spindles (green). This is overlaid (right image)
    with microtubule organizing centers (magenta), sites
    of microtubule binding to chromosomes (gray),
    and chromosomes (blue).
    Together, but still apart
    Upon fertilization, parental chromosomes need to be united. Unexpectedly, in
    mice, male and female chromosomes are kept apart on separate mitotic spindles
    during the first division of the zygote. This increases the probability of forming
    multinucleated cells.
    Published by AAAS
    Downloaded from http://science.sciencemag.org/ on August 6, 2018
    Double trouble at the beginning of life
    Agata P. Zielinska and Melina Schuh
    DOI: 10.1126/science.aau3216
    Science 361 (6398), 128-129.
    ARTICLE TOOLS http://science.sciencemag.org/content/361/6398/128
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