Discovering the difference when egg cells divide

18 July 2019

For women to give birth to a healthy child, their eggs have to 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), have now discovered a previously unknown structure in mammalian eggs that appears indispensable for error-free distribution of chromosomes in this sensitive process. Their discovery and subsequent findings could lead to further understanding of female infertility.

When a new life begins, only half of the genetic information is provided by the egg, the other half comes from the sperm. To this end, the egg has to eliminate half of its chromosomes. This happens during a specialised cell division process called meiosis. However, the process is prone to error, and when too many or too few chromosomes remain in the egg, the resulting embryo often dies early in pregnancy or develops into a baby with a chromosomal disorder, such as Down syndrome.

So explained that when normal body cells divide, the spindle, a complex cellular machine, ensures that the chromosomes are distributed correctly. The spindle consists of protein fibres that fan out towards each other from two spindle poles. It first captures the chromosome pairs and arranges them in one plane. In the next step, half of the chromosomes are pulled to each spindle pole. To distribute the chromosomes correctly, the cell must control exactly how the spindle is set up and how it functions. In most body cells, centrosomes fulfil this task. However, eggs do not have centrosomes. How they managed to control spindle assembly 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 was 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.

Novel structure revealed

Schuh explained: “The egg contains many proteins that are normally found at centrosomes. So we were wondering how these proteins function 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 had distinctive properties. Unlike many other structures in a cell, it was not surrounded by a membrane barrier separating it from its environment. Instead, it appeared to form via phase separation. “This is similar to the de-mixing of oil and vinegar when vinaigrette is prepared.,“ So said. The structure also behaved like a liquid: individual droplets could fuse; and proteins contained in the structure could freely diffuse.

The findings meant that, for the first time, liquid-liquid phase separation was implicated in female meiosis, So said. The cell biologists termed the structure the “liquid-like spindle domain (LISD).

This video shows a mouse egg that segregates its chromosomes (magenta) with the help of the liquid like meiotic spindle domain (green). (Chun So/ Max Planck Institute for Biophysical Chemistry)
Phase separation of a LISD protein in vitro. (Chun So/ Max Planck Institute for Biophysical Chemistry

Same proteins, different organisation

Following the discovery, the researchers surmised that the LISD assisted in controlling the local concentration of spindle proteins in eggs, helping to ensure that precisely the right amount of proteins was 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 regulatory proteins throughout the cell and spindles 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 meiotic spindle, but organise these proteins in a surprisingly different way,” Schuh said. “It will be interesting to investigate if disturbances in the LISD also occur naturally, which could contribute to female infertility.”

Nick Chun So, Croucher Scholarship 2016

Nick Chun So received his BSc in Cell and Molecular Biology, with first-class honours, from the Chinese University of Hong Kong and his PhD from the Max Planck Institute for Biophysical Chemistry in Germany. He is currently undertaking postdoctoral research in the Department of Meiosis, where he works with Dr Melina Schuh, Director of the Institute, to develop new tools for studying meiosis in different mammalian eggs, including humans. So received a Croucher Scholarship in 2016.

To view So’s Croucher profile, please click here.