Developmental biology - Evolutionary Genetics|
Mammalian life begins differently than we thought!
Parental chromosomes do not mix during first cell division...
It was long thought that during an embryo's first cell division, one spindle is responsible for segregating an embryo's chromosomes into two cells. European Molecular Biology Laboratory (EMBL), Heidelberg, Germany, scientists now show that there are actually two spindles, one for each set of parental chromosomes, meaning that the genetic information from each parent is kept apart throughout the first division. Science published the results - bound to change biology textbooks - on 12 July 2018.
This dual spindle formation might explain the high error rate in the early developmental stages of mammals and span the first few cell divisions.
"The aim of this project was to find out why so many mistakes happen in those first divisions," explains Jan Ellenberg, group leader at EMBL who led the project. "We already knew about dual spindle formation in simpler organisms like insects, but we never thought this would be the case in mammals like mice. This finding was a big surprise, showing that you should always be prepared for the unexpected."
Solving a 20-year-old mystery
Scientists have always noticed parental chromosomes occupying two half-moon-shapes in the nucleus of two-cell embryos, but there wasn't an easy explaination.
"First, we were looking at the motion of parental chromosomes only, and we couldn't make sense of the cause of the separation," says Judith Reichmann, scientist in EMBL's Ellenberg group and first author of the paper. "Only when focusing on the microtubules - the dynamic structures that spindles are made of - could we see the dual spindles for the first time. This allowed us to provide an explanation for this 20-year-old mystery."
What is mitosis?
Mitosis is the process of cell division, when one cell splits into two daughter cells. It occurs throughout the lifespan of multi-cellular organisms, but is particularly important as the organism grows and develops.
The key step of mitosis is to pass an identical copy of the genome (all genetic data) to the next cell generation. For this to happen, DNA is duplicated and organised into dense thread-like structures known as chromosomes. The chromosomes are then attached to long protein fibres - the spindle - to pull the chromosomes apart and trigger formation of two new cells.
Micrograph showing condensed chromosomes in blue, kinetochores in pink, and microtubules in green during mitosis - current theory. Image: Wikipedia
What is the spindle?
The spindle is made of thin, tube-like protein assemblies known as microtubules. During mitosis of animal cells, groups of such tubules grow dynamically and self-organize into a bi-polar spindle surrounding the chromosomes. The microtubule fibres then grow towards the chromosomes and connect with them, in preparation for separating chromosomes into two daughter cells. Normally there is only one bi-polar spindle per cell, but this research suggests during the first cell division there are two: one spindle each for the maternal and paternal chromosomes.
New molecular targets
"Dual spindles provide a previously unknown mechanism - and thus a possible explanation - for common mistakes we see in the first divisions of mammalian embryos," Ellenberg explains. Such mistakes can result in cells with multiple nuclei, ending development.
"Now, we have a new mechanism to go after and identify new molecular targets. It will be important to find out if it works the same in humans, because that could provide valuable information for research on how to improve human infertility treatment."
The beginning of life
Furthermore, the knowledge from this paper might impact legislation. In some countries, the law states that human life begins when the maternal and paternal nuclei fuse after fertilisation - and is thus protected from experimentation. If it turns out that this dual spindle process works the same in humans, our definition is inaccurate as the union in one nucleus happens slightly later and after the first cell division.
Impossible until now
This discovery would have been impossible without the light-sheet microscopy technology developed in Ellenberg's and Lars Hufnagel's group at EMBL, now available through the EMBL spin-off company Luxendo. This allows for real-time and 3D imaging of early stages of development, when embryos are very light sensitive and could be damaged by conventional light microscopy. The high speed and spatial precision of light-sheet microscopy drastically reduces the amount of light the embryo is exposed to, making detailed analysis of these formerly hidden processes possible.
At the beginning of mammalian life, the genetic material from each parent meets when the fertilized egg divides. It was previously thought that a single microtubule spindle is responsible for spatially combining the two genomes and then segregating them to create the two-cell embryo. We used light-sheet microscopy to show that two bipolar spindles form in the zygote and then independently congress the maternal and paternal genomes. These two spindles aligned their poles before anaphase but kept the parental genomes apart during the first cleavage. This spindle assembly mechanism provides a potential rationale for erroneous divisions into more than two blastomeric nuclei observed in mammalian zygotes and reveals the mechanism behind the observation that parental genomes occupy separate nuclear compartments in the two-cell embryo.
Authors: Judith Reichmann, Bianca Nijmeijer, M. Julius Hossain, Manuel Eguren, Isabell Schneider, Antonio Z. Politi, M. Julia Roberti, Lars Hufnagel, Takashi Hiiragi, Jan Ellenberg.
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Jul 16, 2018 Fetal Timeline Maternal Timeline News News Archive
Using light-sheet microscopy, the first cell division of a mouse embryo reflects dual
from each parental centromere (PINK) pulling each parental set of chromosomes (PURPLE) apart.
Image: Cartasiova/Hoissan/Reichmann/Ellenberg/European Molecular Biology Laboratory (EMBL).