An overview of corticogenesis


The winners of the first Kavli Prize were announced a couple of weeks ago. One of the three recipients of the prize for neuroscience was Pasko Rakic, a professor of neurobiology and neurology at the Yale School of Medicine.

Rakic has spent most of his career investigating the development of the cerebral cortex of man and other mammals, and it is for his outstanding contribution to this area of research that he has been awarded the Kavli Prize for Neuroscience.

Cortical development (or corticogenesis) is a highly dynamic and complex process, involving the tightly orchestrated movements of billions of cells. Below is a summary of what we currently know about the cell migrations that occur during corticogenesis, with a special emphasis on Rakic's work.

More than 100 years ago, the German neurologist Korbinian Brodmann carried out a comparative study of the cerebral cortex of mammals. He noticed that small regions of the cortex could be characterized by a unique cytoarchitectonic structure and, on the basis of his observations, subdivided the cortex into 52 functionally distinct regions. Brodmann's study was highly influential, and his nomenclature is still in use today. For example, the primary motor cortex is often referred to as Brodmann's area 4, and the primary visual cortex as Brodmann's area 17.

Despite being subdivided in this way, the cortex has the same basic structure throughout. It consists of 6 layers, into which two main types of cell, the pyramidal neurons and interneurons, are organized. Pyramidal neurons are excitatory projection neurons; they synthesize the neurotransmitter glutamate, and their processes extend from the area of the cortex in which the cell body is located to distant parts of the nervous system. Inhibitory interneurons synthesize the neurotransmitter gamma-aminobutyric acid (GABA), and their processes remain within the boundaries of their area of the cortex.

During neural development, vast numbers of immature nerve cells (progenitors) are generated by cell division at the ventricular zone (VZ), a specialized epithelial tissue that lines the cerebral ventricles. Soon after their final cell division, newborn cells embark on a radial migration toward the pial surface on the outer surface of the neural tube. (The pia is the innermost of the three membranes that envelope the brain and spinal cord.) Once they arrive  at the developing cortex, the cells seek out their final destination, and, once there, begin to extend their processes and form synapses with other cells.

The first cohort of cells to leave the VZ forms a structure called the preplate, which will eventually form layer I of the cortex (the outermost layer, nearest the surface of the brain). The second wave of migrating cells splits the preplate into two layers, called the marginal zone and the subplate, and subsequent waves of migrating cells then form layers II-VI. Numerous birthdating studies, using nucleotide analogues such as tritiated thymidine and bromodeoxyuridine, which incorporate themselves into newly synthesized DNA, show that this occurs in an "inside out" manner: cortical layer VI (the innermost layer) is formed first, and then layer V, and so on, such that each wave of cells has to migrate past the one before.

The intermediate zone, which forms between the subplate and VZ, begins to fill with the processes which extend from cells that have settled in the cortex. The white matter tracts in the intermediate zone connect the cells from different regions of the cortex to each other and to subcortical structures.

Cell migration involves three basic processes. First, the cell extends a leading process which explores the immediate environment for guidance cues that provide information regarding the direction of migration; this involves the reorganization of the cytoskeleton, and can be prevented by blocking the polymerization of actin filaments. The nucleus of the cell then moves into the leading process; this is dependent on other cytoskeletal components (microtubules). Finally, the cell retracts its trailing process, and then begins the sequence of events again. 

During corticogenesis, there are at least two modes of radial migration. Cells undergoing somal translocation have a long, branched leading process which spans the thickness of the cerebral wall.and comes into contact with the pial surface, and a short and transient trailing process. These cells move continuously during their migration; time-lapse microscopy shows that the process attached to the pia becomes progressively thicker and shorter as the cell proceeds on its journey.

The other type of radial migration is glia-guided migration. As its name suggest, this type of migration occurs along radially-aligned fibres of specialized cells called radial glial cells. Radial glial cells have their cell bodies in the VZ, and their fibres span the thickness of the neural tube, thus providing a scaffold for migrating neurons. Cells migrating by this mechanism have a short leading process which does not come into contact with the pial surface, and move slowly, with short migratory bursts interspersed with pauses. Once they approach the final stages of their journey, the cells detach themselves from the radial fibres and adopt the somal translocation migratory mode.

After exiting the cell cycle in the VZ, cells recognize their migratory substrate, the glial fibre  and adhere to it via various other cell surface receptors. They then explore the microenvironment to establish the direction in which they will migrate. As they reach the end of their migration, they detect "stop" signals in the cortex, and detach themselves from the radial glial fibre.


Our understanding of glial-guided migration comes largely from Rakic's early work. In the early 1970s, he performed serial electron microscopic sections of the cortex of the fetal monkey brain, and observed that newborn neurons were closely associated with glial fibres throughout their journey. These observations led Rakic to develop the model of glial-guided migration, which was illustrated in the classic figure on the right, from his 1972 paper in the Journal of Comparative Neurology.

The figure is a three-dimensional semi-diagrammatic reconstruction of the relationship between a radial glial fibre and a neuron (with its nucleus labelled N) as it traverses the intermediate zone. At the bottom of the figure can be seen several white matter tracts containing axons which connect different parts of the brain; on the right are cross sections showing the relation of the migrating cell and the glial fibre at each level.

Modern techniques have given us more insight  into the molecular mechanisms of glia-guided migration. We now know that the neuronal protein Astrotactin is required for recognition of the migratory substrate; that the Neuregulins and their ErbB receptors are necessary for the neuron-glial interactions during migration; and that a protein called Derailin is somehow involved in the detachment of neurons from the radial glial fibres.

One candidate for the stop signal is a glycoprotein called Reelin, which is synthesized and secreted by Cajal-Retzius cells, which transiently populate the marginal zone. Although Reelin is essential for the final stages of migration, its exact function remains unclear, but it probably provides some sort of positional information.

New directions

In the past decade, research has revealed that the vast majority of cortical inhibitory interneurons are generated in VZ of the lateral and medial ganglionic eminences (LGE and MGE, respecively). These structures are found in the ventral neural tube (that is, towards the stomach) and eventually go on to form the basal ganglia. The interneurons reach the cortex by means of a tangential migration around the circumference of the developing neural tube.

This novel migration route was established by various tissue culture methods. For example, if the LGE and MGE are labelled with DiI, a fluorescent dye which adheres to cell membranes, labelled cells are later found in most layers ofthe cortex. And if the developing cortex and basal ganglia primordia are separated in slice cultures, there is a significant reduction in the number of interneurons found in the cortex.

Like radially migrating neuronal progenitors, interneurons also adopt an inside out pattern, with early waves of migrating cells populating the deepest layers of the developing cortex. Once they reach the cortex, these cells actively migrate toward the VZ, at a rate of approximately 50 micrometres per  hour (as measured by time-lapse microscopy). Upon their arrival, they pause for some time, before migrating back towards the pial surface and assuming their final position. Exactly why interneurons undergo this ventricle-directed migration is unclear; one hypothesis is that they do so to acquire positional information. instructions regarding which layer of the cortex they should settle in.

Cortical interneurons probably migrate along the corticofugal fibres, which connect the cortex with the thalamus and which express a cell adhesion molecule called TAG-1. The homeobox genes Dlx1 and Dlx2 are also known to be involved in the tangential mirgation of interneurons, as mice in which both these genes have been knocked out accumulate partially differentiated cells in the LGE and have only 25% the normal number of cortical interneurons.

Evolution of the cerebral cortex 

Some clues about the evolutionary origins of the cerebral cortex come from the reeler mutant mouse. In these animals, which have a spontaneous mutation in the reelin gene, radial migration is disrupted; the cell layers of the cortex develop in an "outside in" sequence, and so are inverted. However, the preplate forms normally in these animals. It seems, therefore, that cells migrate by somal translocation in the earlier stages of corticogenesis, when the neural tube is still relatively thin, and then adopt glia-guided migration at later stages, when the cerebral wall is considerably thicker.

Furthermore, somal translocation, with its characteristic ameboid movements, is observed in filmentous fungi such as Aspergillus fumigatus. Together, therefore, these findings suggest that somal translocation is the phylogenetically older mechanism, with glia-guided migration evolving later on with the mammalian lineage.

Radial glial cells may have been instrumental in the evolution of the cerebal cortex. Previously, they were thought of as merely providing a scaffold on which neuronal precursors can migrate long distances, but now it is clear that they also play a part in generating the huge numbers of cortical neurons. Recently, it has emerged that radial glia can themselves divide to produce neuronal progenitors. The radial glial cell bodies, located in the VZ, divide in a number of different ways. In some cases, the daughter cell inherited the radially aligned fibre, and becomes a radial glial cell; in other cases, it does not, but instead becomes a neuronal progenitor which climbs onto the radial fibre of the cell from which it was produced, and then begins its migration.  

20 years ago, Rakic suggested that radial glial cells are involved in specifying the functional subdivisions of the mature cortex. Thus, a proto-map of  the cortex may already be in place at the VZ, where the neurons are born. As the cells migrate, their positioning in relation to one another would be faithfully maintained by the arrangement of the glial fibre scaffold, and so transferred accurately to the developing cortex.

Nadarajah, B., et al. (2002). Ventricle-directed migration in the developing cerebral cortex. Nat. Neurosci. 5: 218 - 224.

Rakic, P. (1972). Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 145: 61-83.

Rakic, P. (1988). Specification of cerebral cortical areas. Science 241: 170-176.

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Have you ever read about how he has tried to crush certain scientists careers? He doesn't have the best reputation as a person - or a fair scientist.

Where did you hear about Rakic's bad rep? I'm curious.

By StudentsTtest (not verified) on 17 Jun 2008 #permalink

Just google Elizabeth Gould for one example.

By Iâ¥BRAINS (not verified) on 21 Sep 2009 #permalink