Neocortical folding – gyrification – is a fundamental evolutionary mechanism that increases cortical surface area and enhances cognitive function. Increased gyrification has been associated with interspecies intelligence. However, it has been challenging to study molecularly in non-spinning animal models.

However, in certain individuals, excessive cerebral cortex folding is associated with neurodevelopmental delay, intellectual impairment, and epileptic convulsions rather than improvement in cognitive function. Most of the genes controlling this folding are unknown.

Scientists from the University of California San Diego School of Medicine and the Rady Children’s Institute for Genomic Medicine are now revealing a protein’s role in human gyrification, establishing cellular polarity and structural integrity of radial glial fibers of the developing brain.

Scientists conducted genomic analyzes on nearly 10,000 families with childhood brain disease over a decade to look for new causes of disease. From their cohort, they found four families with a condition called polymicrogyria.

Polymicrogyria is a condition characterized by abnormal brain development before birth. In polymicrogyria, too many gyri are packed too tightly together.

In particular, all four families had mutations in the Transmembrane Protein 161B (TMEM161B) gene, which makes a protein with previously unknown function on cell surfaces.

After identifying TMEM161B as the cause, scientists determined the cause of excessive folding. They found that the protein controls cell skeleton and polarity, and these control folding.

The scientists found defects in neural cell interactions early in embryogenesis, using stem cells from skin samples from patients and engineered mice.

First author Lu Wang, Ph.D., a postdoctoral researcher in the Gleeson lab, said: “We found that the gene is necessary and sufficient for changes in the cytoskeleton necessary for the way neural cells interact. Interestingly, the gene first appeared in evolution in sponges, which don’t even have a brain, so the protein must clearly have other functions. Here we found a crucial role in regulating the number of folds in the human brain.”

Magazine reference:

  1. Lu Wang, Caleb Heffner, et al. TMEM161B modulates radial glial scaffolding in neocortical development. PNAS. DOI: 10.1073/pnas.2209983120