The
outer layer of the human brain or cerebral cortex, characterized by its
distinctive gyri and sulci (those distinctive ridges and furrows),
controls cognitive and executive function, from conscious thought to
speech to emotional control.
The
cerebral cortex is composed of more than 10 billion cells and 100
trillion-plus connections, a layer of gray matter just five millimeters
thick — a little less than three stacked quarters.
Most
animals with large brains exhibit cortical folding, which allows a very
large area of cerebral cortex tissue (approximately 2.6 square feet) to
be compacted inside the confines of the skull. The more cortical
folding, the more advanced and complex the cognitive functions of the
species. Lower species like mice and rats have smaller, smooth surfaced
brains; higher order species like elephants, porpoises and apes display
different degrees of gyrification or folding of the cerebral cortex.
Humans possess among the most wrinkly of brains, considered an indicator
of advanced evolution.
In
some humans, however, excess folding of the cerebral cortex is
associated not with greater cognitive abilities, but the opposite and
linked to neurodevelopmental delay, intellectual disability and
epileptic seizures. The genes controlling this folding are mostly
unknown.
Writing in the journal PNAS, researchers describe new findings that deepen understanding human gyrification.
Led
by senior study author, researchers performed genomic analysis on
nearly 10,000 families with pediatric brain disease over the course of
10 years to look for new causes of disease.
“From
our cohort, we found four families with a condition called
polymicrogyria, meaning too many gyri that are too tightly packed,” said
the author. “Until recently, most hospitals treating patients with this
condition did not test for genetic causes. The Consortium was able to
analyze all four families together, which aided in our discovery of a
cause for this condition.”
Specifically,
all four families displayed mutations in a gene called Transmembrane
Protein 161B (TMEM161B), which produces a protein of previously unknown
function on cell surfaces.
“Once
we identified TMEM161B as the cause, we set out to understand how
excessive folding occurs,” said the first author. “We discovered the
protein controls the cellular skeleton and polarity, and these control
folding.”
Using
stem cells derived from patient skin samples, and engineered mice, the
researchers identified defects in neural cell interactions early in
embryogenesis.
"We
found the gene is necessary and sufficient for cytoskeletal changes
required for how neural cells interact with one another,” said the
author. “It was interesting that the gene first appeared in evolution in
sponges, which don’t even have a brain, so clearly the protein must
have other functions. Here we found a critical role in regulating the
number of folds in the human brain.”
The
study authors emphasized that genetic discovery studies are important
because they pinpoint causes of human disease, but that these
discoveries can take many years to evolve into new treatments.
“We
hope that physicians and scientists can expand upon our results to
improve diagnosis and care of patients with brain disease,” said the
senior author.
https://www.pnas.org/doi/10.1073/pnas.2209983120