Decreasing levels of that protein, an adhesion molecule called MDGA1, prevents neurons that normally make this protein from assuming their proper position, resulting in brain malformation, researchers report in the April 26th issue of the Journal of Neuroscience.
As Dennis D. M. O'Leary, Ph.D., senior author of the study and a Professor in the Molecular Neurobiology Laboratory put it, "proper neuronal positioning is essential for development of appropriate wiring, which is in turn critical for establishing a normal, functioning nervous system."
Neurons migrate throughout the brain, but migration is particularly important for development of part of the brain known as the cerebral cortex. The cortex sits like a skullcap over the rest of the brain and is responsible for sensory perception, higher-level reasoning, and, in humans, language. In mammals, the largest and evolutionarily newest part of the cortex, the neocortex, is recognized anatomically by its six horizontal layers.
The neocortex develops outward from an underlying zone of cells. From that zone, crawling neurons migrate radially out toward the surface or "superficial" part of the developing cortex, giving rise to a laminar structure. Neurons forming layers 2 and 3, the focus of the current study, are born last and so must elbow their way through cells lying in earlier formed layers to reach what will become the outermost layers. Without MDGA1, these neurons begin to migrate but get stuck before they reach their normal destination.
The MDGA1 gene was cloned and characterized first in rat by O'Leary and two former postdoctoral fellows, E. David Litwack, Ph.D. and Matthias Gesemann, Ph.D. They showed that MDGA1 is a cell adhesion molecule - a protein enabling cells to attach to other surfaces, something that they must do either to move or sit still and elaborate connections. They also showed that MDGA1 is expressed on subpopulations of migrating neurons throughout the developing nervous system, including layer 2/3 neurons in the neocortex, suggesting that MDGA1 may actually be required for migration.
In the current study, O'Leary and Akihide Takeuchi, M.D., Ph.D., a postdoctoral fellow and the study's first author, tested this hypothesis. They first showed that layer 2/3 neurons make MDGA1 protein as they migrate to their destination. Then, utilizing a cutting-edge molecular technique called RNA interference, the Salk researchers silenced the MDGA1 gene. To do this, they painstakingly performed in utero surgery on embryonic mice - injecting an interfering RNA molecule into the lateral ventricle, a fluid-filled space next to the neocortex. Application of an electrical current forced the RNA into neural progenitor cells, and it was subsequently inherited by their neuronal progeny that form layer 2/3 and blocked their ability to make MDGA1 protein.
When Takeuchi and O'Leary examined the neocortex a few days later when the mice were born, they discovered that nearly all neurons containing the interfering RNA were stalled in aberrant deeper locations, indicating that loss of MDGA1 protein had stymied their attempt to travel the full distance to layer 2/3 and supporting the original hypothesis. The goal now is to determine how MDGA1 controls neuronal migration and what the long-term consequences are of its loss.
Impaired function of neuronal adhesion molecules has been previously linked to neurological defects in humans. A cell adhesion molecule known as L1 has been shown to affect cell migration and positioning in other parts of the nervous system. Numerous mutations in the human L1 gene have been uncovered; individuals with these mutations often show severe defects in neuronal positioning and connectivity, which are clinically manifested in conditions such as hydrocephalus, mental retardation and spastic paraplegia.
Whether mutations in MDGA1 lead to brain disorders remains to be seen. "Much work needs to be done, and the appropriate tools need to be developed to do this work," said O'Leary, "but we feel that these studies will eventually provide insight into neurological disorders that have their basis in malpositioning of neurons."
The Salk Institute for Biological Studies in La Jolla, California is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health, and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.