"This study looked at how the cerebral cortex develops and the role of the beta catenin protein to cortical growth," explains senior author Christopher A. Walsh, M.D., Ph.D., a neurogeneticist at Beth Israel Deaconess Medical Center who has been studying cortical development and its role in mental retardation and epilepsy for nearly 10 years.
The largest structure in the brain, the cerebral cortex is the headquarters of our intellect – often referred to as the "gray matter." The large surface area of the cortex houses two-thirds of the brain's 100 billion neurons in a thin layer, only slightly thicker than the peel of an orange. In order for this expanded surface area to fit within the confines of the human skull, the cortex folds in on itself, resulting in a series of ridges and grooves that give the brain its "wrinkled" appearance. This characteristic is unique to humans.
Walsh, who is also the Bullard Professor of Neurology at Harvard Medical School, and Anjen Chenn, M.D., Ph.D., a research fellow in Walsh's laboratory and a pathologist at Brigham and Women's Hospital in Boston, set out to investigate how and why the human cortex grows so large.
Cortical development is fueled by the division of "neural precursor cells," which are the dividing cells that eventually give rise to the brain's neurons. Unlike cells in other tissues of the body, brain cells stop dividing and become fully formed before birth.
This study examined the role of the beta catenin protein to cortical growth. Although this protein is found in many tissues throughout the body – and is also activated in tumors – its function has not been clear. To examine whether activating beta catenin could regulate signaling in the brain's neurons, Walsh and Chenn developed a group of transgenic mice that overexpressed beta catenin in the neural precursor cells.
"The cerebral cortex in the brain of a mouse is normally smooth and flat like a sheet," Walsh explains, describing their findings. "But in humans, the cortex is extremely wrinkled. That's because you're fitting a much bigger sheet into a smaller area. It's like taking a piece of paper and crumpling it into a ball, in terms of surface area. We found that in the mice that overproduced the beta catenin protein, the mouse's cerebral cortex grew dramatically so that instead of a flat sheet, it folded in on itself and appeared 'wrinkled' much like it is in humans."
What may be happening, says Walsh, is that in the cortex, beta catenin acts like a "switch" to tell a cell whether to keep dividing, or to stop dividing and become a neuron. Expressing more beta catenin caused more cells to continue dividing, causing the cortex to keep growing. This same mechanism, he adds, might explain why beta catenin activation is associated with tumors: Although the protein does not increase the actual speed of cell division, it prevents dividing cells from "switching off," causing tissue to grow faster than it should.
"There are diseases of the brain where the reverse is happening," Walsh adds. "In mental retardation, for example, the cerebral cortex is much smaller than normal, so it lacks the brain's normal wrinkled appearance. While we don't yet know whether beta catenin production is abnormal in children with small brains, a better understanding of the regulation of the size of the cerebral cortex has many potential applications to brain development, brain evolution and, possibly, to cancer."
The study was funded by the National Institutes of Neurological Disease and Stroke. Anjen Chenn was a Howard Hughes Medical Institute Physician Postdoctoral Fellow.
Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System. Beth Israel Deaconess is the third largest recipient of National Institutes of Health research funding among independent U.S. teaching hospitals.
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Science