Only one in three fertilizations leads to a successful pregnancy. Many embryos fail to progress beyond early development. Cell biologists at the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen (Germany), in collaboration with researchers from the Institute for Farm Animal Genetics in Mariensee and other international colleagues, have now developed a new model system to study early embryonic development. With the help of this system, they discovered that errors often occur when the genetic material of each parent combines immediately after fertilization. This is due to a remarkably inefficient process.
Human somatic cells typically have 46 chromosomes, which together carry genetic information. These chromosomes are first collected during fertilization, 23 from the father’s sperm and 23 from the mother’s egg. After fertilization, the parental chromosomes initially exist in two separate compartments, called pronuclei. These pronuclei slowly move towards each other until they come into contact. The pronuclear envelopes then dissolve and the parental chromosomes unite.
However, the majority of human embryos end up with the wrong number of chromosomes. These embryos are often not viable, making the erroneous unification of the genome a major cause of miscarriage and infertility.
“About 10 to 20 percent of embryos that have the wrong number of chromosomes result from the egg already containing too few or too many chromosomes before fertilization. We already knew that, ”explains Melina Schuh, MPI director for biophysical chemistry. “But how does this problem arise in so many embryos? The moment immediately following the union of sperm and egg – the zygote stage – appears to be an extremely critical phase for the development of the embryo. We wanted to know why this is the case. “
Overview of a new model system
For their investigations, the scientists analyzed microscopic videos of human zygotes that had been recorded by a laboratory in England. They also sought to find a new model organism suitable for the detailed study of early embryonic development. “Together with our collaborative partners at the Institute of Farm Animal Genetics, we have developed methods to study live bovine embryos, which look very similar to human embryos,” says Tommaso Cavazza, a scientist from the Department of Schuh. “The timing of the first cell divisions is comparable in human and bovine embryos. In addition, the frequency of incorrect chromosome distribution is roughly the same in both systems.” Another advantage of this model system is that the scientists obtained the eggs from which the embryos of cattle developed from slaughterhouse waste, so that no additional animals had to be sacrificed.
Schuh’s team fertilized cattle eggs in vitro, then used live cell microscopy to track how the parental genetic material unites. They found that the parental chromosomes cluster together at the interface between the two pronuclei. In some zygotes, however, researchers noticed that individual chromosomes did not. As a result, these chromosomes were “lost” when the parental genomes united, leaving the resulting nuclei with too few chromosomes. These zygotes quickly showed developmental defects.
“The grouping of chromosomes at the pronuclear interface appears to be an extremely important step,” explains Cavazza. “If reunification fails, the zygotes often make mistakes incompatible with the healthy development of the embryo.”
Depends on an inefficient process
But why do parental chromosomes often fail to cluster properly? The Max Planck researchers were able to find out as well, as Cavazza reports: “The components of the cytoskeleton and the nuclear envelope control the movement of chromosomes in the pronuclei. Oddly, these elements also orient the two pronuclei one We are therefore dealing with two closely related processes that are essential, but often go wrong, so the healthy development of an embryo depends on a remarkably inefficient process.
The scientists’ findings are also relevant for in vitro fertilization in humans. It has been debated for some time whether the accumulation of so-called nucleoli at the pronuclear interface in human zygotes could be used as an indicator of the chances of successful fertilization. Zygotes in which these pronuclear components all congregate at the interface have a better chance of developing successfully, and could therefore be preferentially used for the treatment of fertility. “Our observation that chromosomes must cluster together at the interface to ensure healthy embryonic development supports this selection criterion,” says Schuh.
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