Protecting the vulnerable Y chromosome at the beginning of development

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It's known that the Y chromosome, which confers male sex, plays a big role in development and health, despite its small size. As cells age they frequently lose their Y chromosomes, which is associated with conditions like cancer, Alzheimer's disease and heart disease.

"The Y chromosome is vulnerable as cells divide, with consequences to health," says James Turner, who runs the Crick's Sex Chromosome Biology Laboratory. "But what happens if it's lost in the earliest days of development when it needs to switch on male sex in the embryo?"

Embryos don't usually survive if a chromosome is lost early in development. However, individuals can have a condition where most or some of their cells have only one X chromosome, called Turner syndrome. This affects growth and fertility and causes potential cardiovascular, renal and autoimmune complications.

Turner syndrome is often thought to be linked to the loss of the second X, but it can also result from the loss of a Y chromosome, which James believes may happen more often than previously thought.

May the odds be in Y's favour

In a new study published today in Science Advances, James and Agata Zielinska, a former postdoctoral researcher in the lab, explored how embryos protect the Y chromosome in their earliest days.

"Once a sperm and egg have fused together, the first division into two cells is a huge challenge," says Agata. "And the Y chromosome starts off at a disadvantage, with much lower levels of a protein that helps keep cell division on track."

Before cell division, two copies of each chromosome line up in the middle of the cell and then ropes called 'spindles' pull them apart into each new cell. These spindles attach to a landing pad, or 'centromere', on each chromosome pair. The Y chromosome has unusually low levels of a protein that forms the foundations of the landing pad.

Floating Ys

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So how do embryos with two sex chromosomes emerge if the odds are stacked against the Y?

To find out, Agata fluorescently labelled chromosomes in mouse zygotes (the first cell formed when a sperm and egg fuse) during their first division. She recorded the chromosomes duplicating, lining up in the centre and splitting into two new cells under a microscope. In normal conditions, most Y chromosome pairs separated in the first division.

Agata discovered safeguards that help the vulnerable Y pairs separate successfully, including finely balanced spindle forces, which meant the Y was under less tension than other chromosomes.

But if cells were even mildly stressed, simulated by weakening the spindles, it was a different story. "The Y chromosome pairs often failed to line up and instead floated around the spindle. Notably, embryos were 2.5 times less likely to correct this error before diving, than they were for other chromosomes," says Agata. "This suggests that there is a narrow window where the Y pair separates easily."

Healthy competition

Next, Agata combined an XY and an XO cell to form a 'mosaic' embryo model, containing a mixture of cells with and without a Y chromosome. These embryos were smaller than fully XY embryos. Additionally, with time, the XY cells start to outcompete the XO cells, gradually shifting the balance towards cells with both sex chromosomes. "It's clearly trying to compensate for the loss of the Y chromosome, by favouring cells and X and a Y," Agata says.

This suggests that more embryos than expected may begin as a mosaic of XO and XY cells, but that the developing embryo may be able to partially compensate by prioritising the XY cells. In Turner syndrome, this correction may be incomplete. "The embryo clearly has a remarkable ability to buffer against sex chromosome loss, despite the Y's vulnerability," concludes James.

The lab is now aiming to identify stresses in the body that make it harder for the Y chromosome to complete its crucial first division.

"We'd also love to understand how the loss of the second X chromosome happens in other cases of Turner syndrome," says James. "More generally, this work allows us to shed light on the impact of changes to sex chromosomes from the earliest stages of development through to health in our later years. This is something we're now exploring further in collaboration with Edith Heard's lab at the Crick."