New York, NY, February 15, 2001—In findings that could help lead to better understanding and treatment of brain disorders, Columbia researchers have identified a type of brain cell that generates neurons in most advanced region of the brain, the neocortex. The research, published in the Feburary 9th issue of Nature, shows how this type of cell, called the radial glial cell, may create other neocortical cells during brain development and arranges them in groups called columns, the basic processing units of the neocortex.
The radial glial cells, or radial glia, are thus a kind of neuronal stem cells in the neocortex. That is, they produce the various other types of cells that receive, process and send information. The finding may significantly aid stem cell research, which investigates how such precursor cells might be used to recreate brain areas that are missing or damaged by stroke, trauma, neurodegenerative diseases, and other events.
The initial process in which radial glial cells produce and organize the neocortex occurs in the embryo, the researchers said. But something similar may happen in other parts of the brain and later in life, they added. This possibility could shed light on a discovery that startled scientists last year: that the brain produces new cells throughout life and not only before birth as was long believed.
“Our study… raises the possibility that radial glia should be examined for their potential to generate neurons [brain cells] later in life,” said Arnold R. Kriegstein, M.D., Ph.D., professor of neurology and pathology in the Center for Neurobiology and Behavior, Columbia University College of Physicians & Surgeons. “If you can encourage the injured brain to generate neurons, you may be able to promote recovery.”
Ultimately, the findings could aid research on diseases that may reflect problems in neocortical development and organization, such as epilepsy, mental retardation, schizophrenia, dyslexia, and attention deficit disorder, Kriegstein said.
The neocortex, usually called simply the cortex, is the main seat of thinking and reasoning in humans, a thin sheet of wrinkly tissue that covers the cerebral hemispheres, the top most part of the brain. It exists in all mammals, but it is most developed in humans. The cortex consists of millions of tiny distinct column-shaped regions, aptly called columns, side by side. Each column is a group of cells acting together as a processing unit, like a transistor in a computer. A group of columns also can work together to carry out a particular function, for instance, moving a finger or recalling a memory.
In the embryo, each column grows starting from a group of precursor cells at its base. A precursor divides itself to create new cells. Most of the newcomers, as they mature, rise to sit on top of the column and of their previously created “sibling” cells – although some stray into other columns. As they rise, the cells crawl along long, thin fibers that serve as their guides, helping each find its proper place. The guide fibers are elongated arms of cells that sit at the bottom of the column.
The Columbia group’s key finding is that the cells that provide the guiding fibers, the radial glial cells, are the same ones that generate the other cells. Each radial glial cell provides the guide fiber for its own progeny. Previously, scientists knew the radial glia provided the guide fiber, called a process, but not that it also produced the other cells in the column. Scientists incorrectly assumed that because these other cells are neurons, the type that conduct information, their parent cell could not be a radial glial cell, an entirely different cell type. The radial glia are part of a class of nervous system cells called glia, which support and electrically insulate the information-processing neurons.
The researchers used several experiments to determine that the radial glia are neuronal stem cells involved in neocortical development.
When researchers inserted a bit of DNA into the brains of living mouse embryos, the DNA invaded some brain cells and turned them bright green. This green color would be passed on to infected cell’s descendants, letting researchers identify lineages of related cells. Three days after starting the experiment, researchers found that a typical radial glial cell would have produced four or five immature neurons that were slowly crawling up the glial cell’s process.
A time-lapse movie, filmed as it occurred in thin slices of rat brain in a laboratory culture, provided the most direct evidence. Additional experiments confirmed it also happens in intact, living brains.
This system appears to provide the foundation for how the developing cortex is organized, Dr. Kriegstein said. It also could be relevant in other parts of the brain and in adults.
“Having shown radial glial cells produce neurons in cortex, one could speculate about whether this occurs elsewhere in the nervous system. Radial glia are also found elsewhere in adult brains, in areas where neurons are born in the adult. This may be a more general neural precursor cell.” In addition, knowing that the radial glial cell produces the neurons in its column may be important for studying how information circuits form in the brain.
The research was supported by the National Institutes of Health, the March of Dimes Birth Defects Foundation, the Lieber Center, and the Robert Lee and Clara Guthrie Patterson Trust.