Genetic trick boosts egg count in mice with low fertility

28 October 2015

In this mouse egg cell all the chromosomes are highlighted in green. The shut-down X chromosome is at 10 o'clock. The red cloud covering it is the silencing protein histone H2afx in action.

Image: In this mouse egg cell all the chromosomes are highlighted in green. The shut-down X chromosome is at 10 o'clock. The red cloud covering it is the silencing protein histone H2afx in action.

A genetic trick that restores egg numbers in sub-fertile mice provides a new insight into human infertility.

Scientists at the Francis Crick Institute in London used a mouse model of Turner Syndrome, a common human genetic condition, to investigate problems with egg development. The process of egg cell death they have uncovered in Turner Syndrome mice could explain the cause of infertility in people with abnormal chromosomes.

Women affected by Turner Syndrome have only one X chromosome. The second X chromosome is either entirely or partly missing; this absence causes heart and thyroid problems, physical anomalies and infertility.

Dr James Turner who led the research describes the link between chromosome abnormality and infertility: "Patients can have too few, or too many, chromosomes. Irrespective of the type it is common for a person who has a chromosome abnormality to experience poor fertility. Developing eggs or sperm get stuck at an early stage and die. The research we publish today describes the process behind this death of early egg cells and how we have been able to prevent it in mice.'' 

During healthy egg development chromosomes line up in pairs. There are 20 pairs in the mouse, 23 pairs in humans. If a chromosome is missing or abnormal, checkpoint mechanisms detect a failure to pair and genes in the unpaired sections are shut down, or silenced. If these silenced genes are critical for survival the cell will die leading ultimately to infertility.

Turner syndrome mice shut down the only X chromosome in their early egg cells and lose most of their developing eggs around birth. Dr Turner's team hypothesised that it is this same checkpoint that shuts down the X chromosome and in turn leads to destruction of the egg cells.

Turner explains: ''We discovered that the X chromosome was being silenced in the eggs of Turner Syndrome mice. This meant most of their egg cells weren't surviving. The exciting thing is that we also found a way to stop the egg cells from dying in the mouse model."

Dr Turner and his team removed part of the gene silencing pathway, a protein called histone H2AFX. When histone H2AFX was no longer present the X chromosome wasn't switched off and egg cells developed normally. This genetic trick rescued the eggs in the mouse model; Turner Syndrome mice carried the same number of eggs as normal female mice.

Dr Turner hopes the research could help improve understanding of human infertility: "Our mouse model has shown that early egg cells die simply because genes on the single X chromosome have been shut down. When we deleted the protein that shuts down the chromosome, mice had normal numbers of egg cells.''

Dr Turner concludes: ''It is likely that many of the same genes are affected in human Turner syndrome patients. We are currently attempting to identify which of the silenced genes are critical. The next step, which will be technically challenging, will be to replace them with active copies in the developing egg cells in our mouse models to see if this restores fertility.'' The paper, Histone H2AFX links meiotic chromosome asynapsis to prophase I oocyte loss in mammals, is published in PLOS Genetics.

  • Research in mice has given scientists important insights into infertility caused by chromosome abnormalities such as Turner syndrome. It's hoped that the findings might lead to a way to restore fertility in sufferers.
  • The research was carried out by Francis Crick Institute scientists with colleagues from Technische Universität Dresden in Germany and the National Institutes of Health National Cancer Institute in Bethesda, Maryland, USA.