Researchers have identified a gene that plays a key role in fertility across multiple species and may contribute to our understanding of age-related infertility in women.
The team, based at Washington University School of Medicine in St Louis, were originally searching for genes involved in eye development.
'We blocked some gene expression in fruit flies but found that their eyes were fine' said lead author Dr Helen McNeill. 'They appeared healthy' she said, but 'it turned out they were completely sterile'.
The gene, called nuclear envelope membrane protein 1 (NEMP1), has previously been linked with early menopause in humans, but it was unclear why, or whether it played a role in fertility.
Their study, published in Science Advances, found using fly, fish and mouse models that when the gene was missing, the membrane that envelopes the egg's nucleus looked floppy like a deflated balloon. To investigate further, they grew human cells in a dish that were also missing this gene, then poked a needle through the outer cell membrane followed by the nuclear envelope. Taking note of the amount of force required to penetrate each layer, they found that the nuclear envelope was much softer than normal, whilst the outer membrane was of expected stiffness, suggesting NEMP1 specifically supports nuclear envelope structure.
With age, ovaries develop strands of collagen that can cause mechanical stress not present in embryonic ovaries. 'If you have a softer nucleus, maybe it can't handle that environment' Dr McNeill said. 'This could be the cue that triggers the death of eggs.' she hypothesised. The group are planning to address this question next.
Interestingly, the researchers also found that mice missing the NEMP1 gene were anaemic, meaning they have no red blood cells. 'Normal adult red blood cells lack a nucleus,' Dr McNeill explained. 'There's a stage when the nuclear envelope has to condense and get expelled from the young red blood cell as it develops in the bone marrow.' She theorises that young red blood cells lacking the NEMP1 gene are unable to do this properly, since their 'floppy nuclear envelope' means they're unable to survive this 'mechanically stressful situation'.
Going forward, the team want to investigate NEMP1 mutations and how they may contribute to women's infertility. They have developed human embryonic stem cells with specific genetic variants of NEMP1 listed in genetic databases as associated with infertility. 'We can direct these stem cells to become eggs and see what effect these mutations have on the nuclear envelope.' Dr McNeill said. If these experiments prove NEMP1 mutations cause infertility, future experiments could be aimed at finding ways to fix these mutations. We may be able to 'restore NEMP, for example, or find some other way to support nuclear envelope stiffness' she explained.
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