They discover a mechanism that leads to the formation of folds in the cerebral cortex

Determining the genetic and epigenetic factors that influence brain folding has been the objective of a recent study in which answers have been found to some of those questions that have been pending for a long time.

The study was carried out by a team made up of, among others, Aditi Singh, now at Harvard University Medical School in the United States, and Víctor Borrell, from the Institute of Neurosciences (IN), a joint center of the Higher Council for Scientific Research ( CSIC) and the Miguel Hernández University (UMH) of Elche, in Spain.

This work demonstrates that epigenetic marks are a key mechanism in the instructions that give rise to the folds of the cerebral cortex, and that a protein called Cux2 plays a determining role in this process. Folding is a characteristic of the human brain that, when it fails, produces serious learning and intellectual problems.

Borrell’s team had already developed a protomap that establishes at a genetic level where the gyri and grooves will be generated in the brain during a stage of embryonic development, when they have not yet begun to be generated. “At first the crust is smooth, but there are some areas that will grow a lot and will give rise to turns, while next to it there are others that will grow less and will remain sunken, forming a groove,” explains Víctor Borrell, CSIC research professor at the IN. “This is because there are thousands of genes that are expressed in the cortex of the embryo while it is developing, but they are not expressed in the same quantity in all areas,” he adds.

Thanks to collaboration with Vijay K. Tiwari at the Wellcome-Wolfson Institute of Experimental Medicine at Queen’s University of Belfast (Northern Ireland, United Kingdom), they have been able to take this research one step further. “Now we have observed all the DNA of cells and their epigenetic modifications, which determine the behavior of genes, to understand the mechanisms that give rise to their expression,” says Borrell. They studied the epigenetic mark H3K27ac, an indicator that predicts gene expression, and the results were surprising: in many places where this mark was present, gene expression did not occur. They looked for an answer in a protein, Cux2, which regulates gene expression and whose participation in the differentiation of neurons and formation of neuronal circuits is known.

To verify the influence of Cux2 on brain folding, they introduced the DNA that encodes this protein into the brains of mouse and ferret embryos during gestation. Thanks to this, they confirmed that Cux2 is capable of altering the patterns, forming folds in the mouse cerebral cortex, which is smooth, and completely altering the folding pattern of the ferret. “We have determined that Cux2 is a master factor that has the ability to take advantage of the epigenetic landscape to produce the changes that lead to the expression of thousands of genes that do different things and that the combination of all this makes it possible for the folds to form. “explains Lucía del Valle Antón, IN researcher and co-author of the study.

Using a technique known as “single-cell sequencing” they analyzed the changes that Cux2 causes in the cells to generate the turns. They found that there is a type of stem cells that generate neurons (radial glia cells) that practically disappears, causing other types of these cells to proliferate in greater quantities. This not only affects the type of cell that gives rise to neurons but also the cell lineage they follow, something directly involved with the development of gyri and sulci in the brain.

Image of a ferret brain showing the altered folding pattern (left) by the Cux2 protein. (Photo: IN / CSIC / UMH)

Folding is a characteristic of the human brain whose failure leads to serious learning and intellectual problems. Sometimes patients have genetic mutations that cause malformations in their brain due to a lack of turns. Along these lines, Borrell highlights that carrying out basic research: “it is essential to understand the biology behind these diseases and allows us to be a little closer to finding possible solutions,” he remarks.

The study is titled “Gene regulatory landscape of cerebral cortex folding.” And it has been published in the academic journal Science Advances. (Source: IN / CSIC)