The folds of the human brain are instantly recognisable. Winding ridges and deep grooves give the soft tissue in our heads structure and the appearance of a wrinkled walnut.
In peaks called gyri and crevices called sulci, the outer layer of brain tissue is folded so that straps of it can be squeezed into the skull, and it is here, on the wrinkled surface of the brain, that memory, thinking, learning, and reasoning all take place. .
This folding, or gyrification, is crucial for proper brain function and circuitry – and is thought to be why humans have greater cognitive abilities than monkeys and elephants, whose brains have some folds, and rats and mice, whose brains have a smooth surface do not have one.
Now a team of scientists has discovered why some people have more brain folds than others, in a condition that affects normal brain development called polymicrogyria (PMG).
In polymicrogyria, too many gyri are stacked on top of each other, resulting in an abnormally thick cortex and leading to a wide spectrum of problems such as neurodevelopmental delay, intellectual disability, speech problems and seizures.
“Until recently, most hospitals treating patients with this condition did not test for genetic causes,” explains neuroscientist Joseph Gleeson of the University of California at San Diego (UCSD), one of the researchers behind the new study.
Polymicrogyria comes in many forms, with localized or widespread cortical thickening detectable on brain scans.
Mutations in 30 genes and counting have been linked to the condition. But how all those genetic errors, alone or together, result in the overfolded brain tissue remains unclear. Many cases of PMG also lack an identifiable genetic cause.
It is thought to have something to do with the slow migration of cortical brain cells in early development that leads to a disordered cortex. The cortex is the outer layer of the brain’s bilobed cerebrum, a thin layer of gray matter made up of billions of cells.
To conduct further research, Gleeson teamed up with researchers at the Human Genetics and Genome Research Institute in Cairo to access a database of nearly 10,000 Middle Eastern families affected by some form of childhood brain disease.
They found four families with an almost identical form of PMG, all with mutations in one gene. That gene codes for a protein that attaches to the surface of cells, fancifully named transmembrane protein 161B (TMEM161B). But no one knew what it did.
Gleeson and colleagues showed in subsequent experiments that TMEM161B is found in most fetal brain cell types: in progenitor cells that develop into specialized neurons, in mature neurons that excite or inhibit their neighbors, and in glial cells that support and protect neurons in various ways.
However, TMEM161B comes from a family of proteins that evolutionarily first appeared in sponges – which have no brains.
This puzzled Gleeson and fellow UCSD neuroscientist Lu Wang, who wondered whether the protein might indirectly influence cortical folding by interfering with some fundamental cellular properties that shape complex tissues.
“Once we identified TMEM161B as a cause, we started looking at how excessive folding occurs,” said Wang, the study’s lead author.
Using stem cells taken from patients’ skin samples, the researchers generated organoids, tiny tissue replicas that organize themselves into plastic shells like body tissues and organs do. But the organoids made from patient cells were highly disorganized and showed disrupted radial glial fibers.
In the developing brain, these progenitor cells – which give rise to neurons and glia – usually position themselves at the apex of the cortex and extend radially down to the bottom layer of cortical tissue. This creates a scaffolding system that supports the migration of other newly formed cells as the cortex expands.
But without TMEM161B, the radial glial fibers in the organoids would have lost the sense of how to orient themselves. Further experiments also showed that the cells’ internal cytoskeleton was a mess.
Thus, it appears that without their own internal scaffolding, radial glial fibers cannot provide the scaffolding other cells need to make their way into position in the developing brain.
While this discovery is a promising step forward and gives us clues to how the condition unfolds, it may only be relevant to a small or still unknown proportion of PMG cases.
Much more research is needed to clarify our understanding of how many people with PMG are affected by mutations in TMEM161B – but now that researchers know what to look for, they can sift through other datasets in search of more cases.
“We hope that clinicians and scientists can extend our results to improve the diagnosis and care of patients with brain disease,” says Gleeson. That’s a long road, but a hopeful one.
The study is published in PNAS.