Uncovering unknown stages of foetal development

By applying gene analysis to individual cells from early mouse embryos, an international research team has discovered previously unknown cellular stages of foetal development from fertilised egg to living being.

All over the world, researchers are trying to find all the pieces of the puzzle describing how a fertilised egg develops into a healthy being, in order to gain a detailed understanding of the differentiation process from the totipotent stem cell. This knowledge is essential to understanding the mechanisms behind congenital diseases, foetal malformation and eventually, how to treat diseases using stem cells.

Now, researchers led by the Karolinska Institutet’s Dr Qiaolin Deng have revealed new details of the critical phase between the attachment of the embryo to the uterus and the formation of the first anatomical axis, at which point the embryonic cells begin their journey towards creating a body, with a front and a back.

“It’s a critical period when the whole anatomical plane is created,” Dr Deng said. “If it doesn’t go smoothly, it can cause foetal malformation or death.”

However, the developmental states of the cells that take part in the process are not always the same. In order to map what happens in individual cells, the researchers used single-cell RNA sequencing on a total of 1724 cells from 28 mouse embryos in four early stages of development (5.25 to 6.5 days old). An average of 8577 genes were expressed in each cell.

Using bioinformatic analysis, the cells were then sorted into different cell types on the basis of which genes were active or inactive, allowing the researchers to see the order in which the genes were switched on. The result, published in the journal Cell Reports, was a molecular roadmap of the events that control cell differentiation.

“The study has revealed previously unknown details about what happens before the early embryo gains its first spatial orientation, and shown that the cells along the future head-tail axis have different differentiation potential,” Dr Deng said.

At the same time as the anatomical axis starts to form, another process gets underway in the female embryo, which contains two X chromosomes — one from each biological parent. Previous studies on mice have shown that the paternal X chromosome is first switched off completely in the embryo so that female embryos do not have twice the genetic activity as male. The paternal X chromosome copy remains switched off in the cells that form the placenta and the yolk sack, but is reactivated in the embryo’s cells. Then a random inactivation of the maternal or paternal X chromosome occurs. Female embryos therefore comprise a ‘mosaic’ of cells, in which either the maternal or paternal X chromosome is active.

The study shows that the first inactivation of the paternal X copy does not happen to the extent previously believed, with Dr Deng saying that “the paternal X chromosomes that are reactivated never have been completely switched off. The random inactivation also takes place at different rates in the embryo’s cells.”

The results of the study thus shed new light on the early development of the embryo in animals — humans included. This will be “indispensable for understanding miscarriages and congenital disease”, according to Dr Deng, who noted, “Around three in every 100 babies are born with foetal malformation caused by faulty cellular differentiation.”

Image credit: ©videodoctor/Dollar Photo Club

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