The genes that protect the differentiation process of the cells of the embryo

Scientists have analyzed the factors that give plasticity to pluripotent cells and their role in the choice of cell lineages.

The study has been led by the Severo Ochoa Molecular Biology Center, a mixed center of the Higher Council for Scientific Research (CSIC) and the Autonomous University of Madrid (UAM), and in collaboration with the National Center for Cardiovascular Research, in Spain all these institutions.

The study authors have discovered that the genes that make a cell pluripotent and have the ability to become any other type of cell during the embryonic stage also influence the process by which cells choose their cellular identity and that of their descendants.

After fertilization, the zygote is generated, a single cell from which a complete organism will develop. In the first divisions, the cells are equivalent, they have a great capacity to proliferate and a plasticity that allows them to develop cells as different as a neuron or a hepatocyte. However, this power is progressively lost throughout embryonic development, as cells make lineage decisions and differentiate.

“Until now it was thought that these genes only made the cell pluripotent, but we have seen that they also influence the following process, that of differentiation. After implantation in the uterus, the embryo goes through a process called gastrulation, in which the cells choose their destiny within the body and at this moment pluripotency ceases to exist as such. However, the expression of pluripotency factors continues a little longer over time and our goal has been to understand why these factors continue to express themselves and what their function is beyond pluripotency”, explains CSIC researcher Miguel Manzanares, from the Molecular Biology Center.

Mouse embryo with the Hoxb1 gene expressed normally (left) and mouse embryo where it is expressed out of place (right) by the action of OCT4. (Photos: CBMSO (CSIC-UAM))

The ability to generate any type of cell is maintained in the embryo thanks to the action of the so-called pluripotency factors (OCT4, NANOG and SOX2, among others) that are only expressed in the early stages of development, while in an adult organism they are off. This research has focused mainly on OCT4, which is one of the four factors that were overexpressed in 2006 by Shinya Yamanaka to reprogram adult fibroblasts (cells that contribute to tissue formation) and convert them into induced stem cells, work by which he was awarded the Nobel Prize for Physiology and Medicine in 2012.

To study this process in detail, the research team has characterized both in vivo and in vitro how the OCT4 factor influences the regulation of Hox genes, which are responsible for giving identity to the cells of the anteroposterior axis of the embryo.

“There are numerous works on pluripotency, however, much less is known about how this network is disassembled to allow the determination of a specific cell lineage. Understanding pluripotency is the Rosetta stone to unravel such important and complex processes as tissue regeneration, rejuvenation or cancer”, concludes Manzanares.

The study is titled “Pluripotency factors regulate the onset of Hox cluster activation in the early embryo”. And it has been published in the academic journal Science Advances. (Source: Marta García Gonzalo / CSIC)