Development of the Cerebral Cortex
Defects of the central nervous system remain the leading cause of death and disabilities for infants under the age of one year. To better understand what causes these problems, the cellular and molecular events that underlie normal nervous system development must become better understood by studying different animal models of nervous system development. Only then can we conceivably be able to design therapeutic regimes to reduce the prevalence of developmental abnormalities.
The mammalian brain
is dominated in size by one of its major subdivisions, the cerebral cortex. (See Figure 1.) Yet the complexities of its development as well as its structural and functional organization are just beginning to be revealed.
In more recently evolved or "higher" animals the cerebral cortex (area in red) consists of a larger proportion of the brain. In larger mammals, the surface of the cerebral cortex becomes folded and thusly creates grooves (sulci) and bumps (gyri).
The four lobes comprising the cerebral cortex are involved in complex brain functions, including memory, awareness, thinking, language and consciousness.
Brain cells or neurons destined to form the cerebral cortex must successfully divide, move or migrate to their destination, develop polarized processes characteristic of brain cells, (axons and dendrites), express molecules on their cell surface and inside themselves to promote cell-to-cell communication and establish appropriate and functional contacts with many other brain cells as maturation unfolds.
The developing mouse cortex is stained (See Figure 2.) to show which cells contain the molecule, gamma-amino butyric acid (GABA), that is considered to play a potential role in the movement or migration of these cells to their destination.
With all of the responsibilites that an organism's genes require to coordinate these complex events that must necessarily occur at the proper time and in the proper place, it is no small wonder that both environmental and genetic disturbances which disrupt even one of the multiple events, like neuronal migration, can contribute to diseases that include epilepsy
, schizophrenia
, and developmental disabilities related to these brain malformations.
Research in this laboratory concentrates on the development of the earliest neurons to move and begin to form the cortex of embryonic mice. These first neurons of the cerebral cortex represent the initial framework (See Figure 3.) that provides a structural organization fundamental for the numerous subsequent waves of migrating neurons to reach their proper place and establish proper connections).
This drawing show how the organization of the developing cerebral cortex changes dramatically as cell divide, migrate and differentiate in their final destination.
Both normal as well as genetic mutant mice, where these earliest neurons do not move to their proper destination, are studied with a variety of light microscopic and electron microscopic approaches. These include real-time "movies" of migrating brain cells that have been labeled with fluorescent dyes using in vitro brain slices, immunocytochemical staining of brain sections for specific molecules at different stages of cortical development, and computer-aided image analysis of cells as they grow their axons and dendrites; all of which help to analyze the interactions between cells (See Figure 4 for high power view of a migrating neuron in the embryonic mouse cortex.) as they move from their birthplace to their final destination.
This picture taken with the Philips electron microscope shows a young migrating neuron in the mouse cerebral cortex magnified X14,000. Its cell body contains a nucleus that is the grayish-flecked oval area and its leading process is relatively long. Migrating neurons contact other cell bodies and fibers from other brain cells called radial glia to help them move to their final location.
As more genetically-modified mouse strains become available from other neuroscientists that show specific alterations in normal patterns of cell migration during formation of the cerebral cortex, these approaches can be applied to these new strains to further understand the important role that specific genes and molecules play in the assembly of the cerebral cortex.
Advances in the understanding of the structural and molecular composition of prenatal cells and axons involved in the determination of the complex but elegant organization of the cerebral cortex in normal and abnormal development will increase our knowledge about developmental disorders that affect the vulnerable fetal brain. Such fundamental knowledge will eventually enable scientists to repair abnormal cells and molecules, thereby leading to prevention and treatment of many neuronal migration disorders
that presently lead to mental retardation and developmental disabilities.