For women to give birth to a healthy child, their eggs have to precisely halve their set of chromosomes before fertilisation. Cell biologists at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, including Nick Chun So (Croucher Scholarship 2016; Max Planck Croucher Postdoctoral Fellowship 2020), have now discovered a previously unknown structure in mammalian eggs that appears indispensable for this error-prone process. Their discovery and subsequent findings could lead to further understanding of female infertility.
When an egg is fertilised by a sperm, their genetic materials reunite to give a diploid zygote, which will normally develop into an embryo and become the fetus. However, if the fertilised egg contains too many or too few chromosomes, which is often a result of error-prone meiosis, the resulting embryos will die early in pregnancy or develop into a baby with chromosomal disorder, such as Down syndrome.
So explained that when normal body cells divide, the spindle, a complex cellular machinery, ensures that the chromosomes are distributed correctly. The spindle consists of protein fibres that fan out towards each other from two poles. It first captures the chromosomes and arranges them in one plane. In the next step, half of the chromosomes are pulled towards each pole. To execute these processes properly, the cell must control how the spindle is set up. In most body cells, centrosomes fulfil this task. However, eggs do not have centrosomes. How they manage to assemble their spindle had been unclear.
Now in research led by Dr Melina Schuh, Director of the Max Planck Institute for Biophysical Chemistry, scientists have discovered a previously unknown structure in the eggs of mice and other mammals. This structure is essential to organise the spindle, ensuring that the correct number of chromosomes ends up in the egg so that a healthy embryo can develop. The study’s findings have been published in Science, with So as the first author.
Schuh explained: “The egg contains many proteins that are normally found at centrosomes. So we were wondering what are the functions of these proteins in egg cells, where centrosomes are absent. To our surprise, we observed under the microscope that 19 proteins localised to an unusual structure in the spindle region.”
The newly discovered structure has distinctive properties. Unlike many other structures in a cell, it is not surrounded by a membrane that separates it from the cytoplasm. Instead, it appears to form via liquid-liquid phase separation. “Proteins within this structure de-mix from the cytoplasm, similar to the de-mixing of oil and vinegar when vinaigrette is prepared.” So said. The structure also behaves like a liquid: individual protrusions could fuse; and proteins could freely diffuse within this structure.
The findings meant that, for the first time, liquid-liquid phase separation is implicated in female meiosis, So said. The cell biologists termed the structure the “liquid-like spindle domain (LISD)”.015_LISD segragation
This video shows a mouse egg in the process of meiotic division. The video on the left shows the liquid-like meiotic spindle domain (green) with the chromosomes (magenta), while the video on the right shows the location where meiotic division occurs inside the cell. From the video, it is shown that the mouse egg cell segregates its chromosomes with the help of the liquid like meiotic spindle domain. (Chun So/ Max Planck Institute for Biophysical Chemistry)
Following the discovery, the researchers surmised that the LISD assists in controlling the local concentration of spindle proteins in eggs, helping to ensure that precisely the right amount of proteins is available to form the spindle.
The importance of the LISD for chromosome segregation in eggs was then shown when the researchers disrupted the LISD. This led to dispersion of spindle proteins throughout the cell and the spindle could no longer form properly. As a result, most eggs failed to distribute the chromosomes correctly.
“It appears that mammalian egg cells use the same proteins as normal body cells to assemble the specialised meiotic spindle, but organise these proteins in a surprisingly different way,” Schuh said. “It will be interesting to investigate if disturbances in the LISD occur naturally in human, which could contribute to female infertility.”
Nick Chun So received his BSc in Cell and Molecular Biology, with first-class honours, from the Chinese University of Hong Kong and his doctoral degree, with summa cum laude, from the University of Göttingen in Germany. He is currently undertaking postdoctoral research at the Department of Meiosis, where he continues to work with Dr Melina Schuh, Director of the Max Planck Institute for Biophysical Chemistry, to develop new model systems for studying earlier stages of female germline development. So received a Croucher Scholarship in 2016 and a Max Planck Croucher Postdoctoral Fellowship in 2020.
- Dr So’s personal page (The Croucher Foundation): https://scholars.croucher.org.hk/scholars/chun-so
- The scientific article Dr So published in Science in 2019: https://science.sciencemag.org/content/364/6447/eaat9557