NEUROGENETICS '99 Periventricular Heterotopia and the Genetics of Neuronal Migration in the Cerebral Cortex

In recent years, remarkable contributions to our understanding of how the brain develops have come from the field of genetics. The study of brain development is important, not only to further our understanding of this complex phenomenon, but because gross brain malformations are now recognized to cause significant proportions of cognitive and neurologic disorders. When the cerebral cortex fails to form properly, the result is often severe mental retardation. Even mild dysgenesis of the cortex is frequently associated with epilepsy.Modern genetics affords us the opportunity to explain these developmental mishaps at a molecular level and provides critical insight into nature’s program for brain development, adding an important new dimension to the extensive neuroanatomic work of the last 100 years. Neurons that populate the adult cortex are not born in place. Instead, they are born deep within the brain, in the germinal layer of the ventricular zone, which develops from the lining of the lumen of the neural tube. To get to their proper adult location, most cerebral cortical neurons migrate hundreds to thousands of cellbody lengths along tracks of radially oriented glial cells,which stretch from the ventricular zone to the outer, pial surface. These cortical neurons migrate in waves to build layers in the cortex, with each successive wave migrating past earlier-born neurons to add a more superficial layer (fig. 1A). This migration pattern is referred to as “inside out” and must be faithfully executed for the adult cortex to form and function properly. When migration is complete, the cortex is a six-layered structure (fig. 1B), with each layer comprising different types of neurons that form discrete connections within the CNS and perform distinct functions.