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GENETICS Commoner in Brain Coronates CortexDevelopment of Cerebral Cortex May Be Regulated by Brain's Humble Roof Plate Of all the structures that form the central nervous system, the cerebral cortex is the star. With its role in higher cognitive functions, the cortex represents a significant evolutionary development in mammals, culminating in the enlarged hemispheres of humans and other primates. In the development of this crowning structure, neurons are guided by factors that are both genetic and environmental. The lab of Christopher A. Walsh, the Bullard professor of neurology at Beth Israel Deaconess Medical Center, has discovered that one gene in particular is necessary to form the cortex, serving as a selective switch for cortical development. In the Nov. 20 Neuron, Walsh and his colleagues report, ironically, that the regulation of this powerful gene is orchestrated by one of the brain's humblest structures.
Roof becomes wall. In the developing brain, an epithelial layer called the roof plate (red) burrows into the top of the cerebral cortex and divides it in two, creating the cortical hemispheres. New research suggests that the roof plate has a role in creating the cortex rather than simply shaping it. Walsh and Edwin Monuki, a former postdoc in Walsh's lab who recently started his own lab at the University of California, Irvine, wanted to understand the role of Lhx2, a homeobox gene that patterns the upper regions of the forebrain. Without the gene, the brains of mice were stunted, forming what looked like a very small cortex. Closer inspection revealed that the area that would normally flourish with cortical neurons and form a dazzlingly complex brain structure instead formed an unremarkable layer of epithelium that extended the roof plate of the brain. Forming SidesThe roof plate's most significant role in development is to act as a wedge that splits the cortex in two. This division is accomplished during development when the roof plate inserts itself into the upper midsection of the brain and drives down, forming a heart-shaped structure and eventually, two separate lobes. After this process, part of the roof plate remains buried within the cortex as the choroid plexus, which secretes cerebrospinal fluid that bathes the brain and maintains the blood-brain barrier.Although the roof plate is known to have additional effects in other parts of the central nervous system, little is known about its role in cortical development beyond this mechanical one. Because the Lhx2-mutant mice formed an enlarged roof plate instead of a cortex, Lhx2 seems to make a key determination: "whether you're going to become the most sublime part of the brain or the most mundane part of the brain," said Walsh. "That decision is made by one single gene." A small number of cortical neurons did remain in the Lhx2 mutants--specialized neurons that play a critical role in patterning and organizing all the other neurons in the cortex. But the cells were oriented sideways, suggesting that they did not migrate out from a central point as most cortical neurons do. Further investigation showed that some of the remaining cells had migrated into the cortex from the roof plate region itself. The unexpected origin of these cells may represent a more efficient way of introducing specialized neurons into the cortex.
Working with mice, a team led by Christopher A. Walsh has discovered a gene critical for growth of the cerebral cortex. Photo by Graham Ramsay Razing the RoofAfter finding the roof plate's role as a source of neurons, the team decided to investigate whether this relative wallflower of the brain had other, more active roles by seeing what would happen if the roof plate were removed. They used a mouse created by Thomas Jessell of Columbia University, a model whose roof plate had been eliminated through genetically targeting the expression of a toxin only to the roof. By studying the cortical areas more closely, Walsh's team found that the relationship between the roof plate and the cortex was even more complex than previously thought.The team found that removing the roof plate made the cortex much smaller. When they analyzed expression levels of Lhx2 in the mice, they found that the gene was expressed, but in a very different pattern. Normally, Lhx2 levels follow a gradient in the cortex. Without the roof plate, the levels were lower and evenly distributed. The roof plate is thought to affect patterning in the spinal cord through secreting certain bone morphogenic proteins (BMPs). Assuming that these proteins might also mediate the roof plate's signals to Lhx2 in the cortex, Walsh's group exposed cultured slices of cortex to beads soaked in bone morphogenic proteins. The cultured neurons expressed Lhx2 in a bull's-eye pattern, with no Lhx2 at the site of the bead and high levels a bit farther away, which tapered off at a distance. The pattern is strikingly similar to the gradient of Lhx2 in vivo. "Lhx2 responds to BMPs in a culture much the same way Lhx2 responds to the roof plate in the animal," Walsh said. The finding suggests that bone morphogenic proteins are the mediator of cortex regulation by the roof plate. The existence of a gene that has such a powerful role in cortical development raises the question of whether it figures into human disease. "It has a very selective effect on the cortex," said Monuki. He and Walsh are both investigating possible mutations that might have a role in human abnormalities. It will also be intriguing to study the gene from an evolutionary context as a master switch for the cortex. Finally, knowing that Lhx2 expression is a key part of a cortical neuron's development may have implications for stem cell therapies and other methods of manipulating cells. "This is a gene that basically tells a neuron, you're going to be part of the cortex," said Walsh. "I think that's an important concept to have a handle on if we want to replace lost neurons in the cerebral cortex." --Courtney Humphries |
