Neuroscientists at the Scripps Research Institute in La Jolla, California have identified a new stem cell population in the brain that might differentiate into those neurons responsible for higher thinking. Also, by culturing these neurons in the laboratory, scientists might be able to design better treatments for those cognitive disorders, such as schizophrenia and autism that result from abnormal connections among particular brain cells.
This new research also illustrated how neurons in the uppermost layers of the cerebral cortex form during embryonic development of the brain.
Senior author of this work, Ulrich Mueller, professor and director of the Dorris Neuroscience Center at Scripps Research, commented: “The cerebral cortex is the seat of higher brain function, where information gets integrated and where we form memories and consciousness. If we want to understand who we are, we need to understand this area where everything comes together and forms our impression of the world.”
Previously, scientists thought that all cortical neurons, whether they occupied the lower or upper layers of the brain, were derived from the same stem cell; a cell called the radial glial cell (RGC). The fate of neurons were thought to result from when they were born with the earliest neurons migrating only a little and staying close to where they were born (lower layers), and later born neurons migrating further from where they were born (uppermost layers).
Mueller’s research team, however, has identified a neural stem cells that specifically gives rise to neurons that make the upper layers of the cerebral cortex, regardless of the time or place of birth.
Santos Franco, a senior research associate in the Mueller Laboratory said, “Advanced functions like consciousness, thought, and creativity require a lot of different neuronal cell types and a central question has been how all this diversity is produced in the cortex. Our study shows this diversity already exists in the progenitor cells.”
According to Mueller: “The [older] model was that there is a stem cell in the center of the ball that generated the different types of neurons in successive waves. What we now show is that there are at least two different populations of RGCs and potentially more.”
Franco used a mouse strain that he had constructed in which he could track upper-layer neurons as they were born and as they migrated. A marker gene called Cux2 is only expressed by upper-layer neurons, and Franco used an enzyme from bacterial viruses called the Cre protein to flip on a red-glowing protein when Cux2 is expressed.
To their surprise, a population of RGCs flipped on Cux2 at the earliest time of their development (embryonic day 9-10). The problem is that no upper layer neurons exist at this early time in development, which means that these cells are programmed to form upper layer neurons even though no such tissue exists at this time. Non-Cux-2-expressing neurons became lower layer neurons.
Culturing Cux-2-expressing neurons in the laboratory they formed the types of neurons normally found in the upper layer of the brain. Likewise, non-Cux2-expressing neurons formed other types of neurons normally found in the lower layers of the brain.
During development, Cux2-positive stem cells proliferate and self-renew before they differentiate into neurons. Does the birthday of the neuron determine it’s eventual developmental fate? To determine if this is the case, Mueller and his colleagues used a molecule called TCF4 to force premature differentiation of the Cux2-expressing cells. Even under these conditions, the Cux2-expressing cells still formed upper layer neurons.
Thus regardless of their birth date or location of their birth, they still form upper layer neurons. As Mueller puts it, these RGCs have some intrinsic property that determined their cell fate from the start.
This RGC subset is responsible for the huge proliferation of cells required to generate the larger upper-layer cortex found in the brains of primates. With bigger brains, however, comes the risk of disorders from upper-layer neuron connection abnormalities. TO date, researchers have only managed to generate lower-layer neurons from stem cells in the laboratory. According to Mueller, “The opens a door now to try to make the upper-layer neurons, which are frequently affected in psychiatric disorders.”