The brain is not just a lump of flesh but comprises many small and large folds and fissures that give the brain its characteristic shape. The folds are related to higher cognitive function and the risk of developing neurological disorders such as autism, attention-deficit/hyperactivity disorder and epilepsy. New research shows which genes determine how the brain folds.
The brain’s folds and fissures may look arbitrary, but the pattern of the folds is the same for all humans and within other large mammals.
For many years, researchers did not attach much importance to these folds, but recent research has shown that the folds are associated with intelligence. Animals with more folds are often more intelligent.
Research has also shown that many people with either low intelligence or neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD), autism or epilepsy have a malformed folding pattern.
A new study now shows which genes determine whether the brain folds correctly during brain development. The research may form the basis for new investigations into the causes of neurodevelopmental disorders.
“The folding of the brain is associated with cognitive performance, and misfolding is associated with neurodevelopmental disorders. This makes investigating what underlies whether the brain folds correctly during development very interesting for us,” explains a researcher behind the study, Vijay Tiwari, Professor, Department of Molecular Medicine, University of Southern Denmark, Odense.
The research has been published in Science Advances.
Brain comprises unique folds and fissures
Brain folding starts at the early stage of fetal development and determines the final design of the entire brain.
Many genes determine the shape of the brain so it can function optimally, and the researchers examined the brains of ferret embryos.
Although the brains of animals generally differ from those of humans, the brain of a ferret is similar to that of humans in terms of both tissue anatomy and folding, and examining the landscape of cerebral cortex folding in ferrets offers a unique opportunity to decode the mechanisms behind brain folding among humans.
The researchers investigated what creates the gyri (folds) and the sulci (fissures) in the brain during brain development by examining which genes were active in the embryonic brain in the areas that form the gyri and in the areas that form the sulci.
Specific genes cause misfolding
The results revealed that the epigenetic mechanisms differ between the two regions of the brain before the folding patterns become morphologically apparent.
According to Vijay Tiwari, this shows that distinct pre-existing developmental regulators determine brain folding during development.
The researchers also identified several genes involved in this developmental regulation, including the transcription factor Cux2, which regulates the expression of several other critical genes.
Cux2 is more highly expressed in the regions of the brain that form the sulci versus the gyri, but after the researchers overexpressed Cux2 during development, the brain got misfolded.
According to Vijay Tiwari, this clearly indicates that Cux2 is important for correct brain folding and creating the right folds and fissures for an optimally functioning brain.
“We could reproduce some of the same malformations we find among people with cognitive dysfunction. This is the first time anyone has linked a large number of specific genes and epigenetic mechanisms in brain folding and to potentially associated developmental disorders,” he adds.
May lead to improved understanding of developmental disorders
Vijay Tiwari says that having a list of genes that determine brain folding forms the basis of a new research field in understanding neurodevelopmental disorders.
The next step in the research will be to determine whether the same genes are known to increase the risk of developing neurodevelopmental disorders.
“For the first time, we can obtain insight into how errors in genes can lead to brain misfolding with implications for higher cognitive functions and the risk of developing many neurodevelopmental disorders,” notes Tiwari, adding that further research may help to identify specific biomarkers for various developmental disorders and new therapeutic strategies.
For example, if a specific gene is relevant for correct brain folding during development and genetic studies link the same gene to an increased risk of developing autism, improved understanding of the role of this gene can act as a biomarker when diagnosing autism and will improve understanding of what leads to the development of autism.
“The primary aim is to find genetic biomarkers for the development of neurological disorders so that we can identify people with these disorders and understand why they develop them. In the long term, this might pave the way for therapy, perhaps restoring the functions of the brain lost when the brain was misfolded,” concludes Vijay Tiwari.
