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Real-time imaging of migrating neurons has changed our understanding of how newborn neurons reach their final positions in the developing cerebral cortex. The migratory routes and modes of migration are more diverse and complex than previously thought. The finding that cortical interneurons migrate to the cortex from origins in the ventral telencephalon has already markedly altered our view of cortical migration. More recent findings have demonstrated additional nuances in the migratory pattern and highlighted differences between subsets of interneurons. Moreover, radial migration of pyramidal neurons does not progress smoothly from ventricle to cortical plate, but is instead characterized by distinct migratory phases in which neurons change shape and direction of movement. Integrating these findings with the molecular machinery underlying migration will provide a more complete picture of how the cerebral cortex is assembled.

Precise patterns of cell division and migration are crucial to transform the neuroepithelium of the embryonic forebrain into the adult cerebral cortex. Using time-lapse imaging of clonal cells in rat cortex over several generations, we show here that neurons are generated in two proliferative zones by distinct patterns of division. Neurons arise directly from radial glial cells in the ventricular zone (VZ) and indirectly from intermediate progenitor cells in the subventricular zone (SVZ). Furthermore, newborn neurons do not migrate directly to the cortex; instead, most exhibit four distinct phases of migration, including a phase of retrograde movement toward the ventricle before migration to the cortical plate. These findings provide a comprehensive and new view of the dynamics of cortical neurogenesis and migration.

Early in development of the central nervous system, radial glial cells arise from the neuroepithelial cells lining the ventricles around the time that neurons begin to appear. The transition of neuroepithelial cells to radial glia is accompanied by a series of structural and functional changes, including the appearance of "glial" features, as well as the appearance of new signaling molecules and junctional proteins. However, not all radial glia are alike. Radial glial lineages appear to be heterogeneous both within and across different brain regions. Subtypes of neurogenic radial glia within the cortex, for example, may have restricted potential in terms of the cell types they are able to generate. Radial glia located in different brain regions also differ in their expression of growth factors, a diverse number of transcription factors, and the cell types they generate, suggesting that they are involved in regionalization of the developing nervous system in several aspects. These findings highlight the important but complex role of radial glia as participants in key steps of brain development., (Copyright 2003 Wiley-Liss, Inc.)

Radial glial cells play at least two crucial roles in cortical development: neuronal production in the ventricular zone (VZ) and the subsequent guidance of neuronal migration. There is evidence that radial glia-like cells are present not only during development but in the adult mammalian brain as well. In addition, radial glial cells appear to be neurogenic in the central nervous system of a number of vertebrate species. We demonstrate here that most dividing progenitor cells in the embryonic human VZ express radial glial proteins. Furthermore, we provide evidence that radial glial cells maintain a vimentin-positive radial fiber throughout each stage of cell division. Asymmetric inheritance of this fiber may be an important factor in determining how neuronal progeny will migrate into the developing cortical plate. Although radial glial cells have traditionally been characterized by their role in guiding migration, their role as neuronal progenitors may represent their defining characteristic throughout the vertebrate CNS.

Recent work suggests that radial glial cells represent many, if not most, of the neuronal progenitors in the developing cortex. Asymmetric cell division of radial glia results in the self-renewal of the radial glial cell and the birth of a neuron. Among the proteins that direct cell fate in Drosophila melanogaster that have known mammalian homologs, Numb is the best candidate to have a similar function in radial glia. During asymmetric divisions of radial glial cells, the basal cell may inherit the radial glial fibre, while the apical cell sequesters the majority of the Numb protein. We suggest two models that make opposite predictions as to whether the radial glia or nascent neuron inherit the radial glial fiber or the majority of the Numb protein.

Purpose: Cortical dysplasia (CD) is associated with epilepsy in both the pediatric and adult populations. The mechanism underlying seizures with cortical malformations is still poorly understood. To study the physiology of dysplastic cortex, we developed an experimental model of CD., Methods: Pregnant rats were given intraperitoneal injections of carmustine (1-3-bis-chloroethyl-nitrosourea; BCNU) on embryonic day 15 (E15). Cortical histology was examined in the resulting pups at P0, P28, and P60. In addition, evoked and spontaneous field potential recordings were obtained in cortical slices from adult control and BCNU-exposed rats. Finally, we used whole-cell recordings to compare physiologic properties of pyramidal neurons and gamma-aminobutyric acid (GABA) responses in control and BCNU-treated animals., Results: Features characteristic of CD were found in the offspring, including laminar disorganization, cytomegalic neurons, and neuronal heterotopias. Dysplastic cortex also contained abnormal clusters of Cajal-Retzius (CR) cells and disruption of radial glial fibers, as demonstrated with immunohistochemistry. Under conditions of partial GABAA-receptor blockade with 10 microM bicuculline methiodide (BMI), slices of dysplastic cortex demonstrated a significant increase in the number of spontaneous and evoked epileptiform discharges. Individual pyramidal neurons in dysplastic cortex were less sensitive to application of GABA compared with controls., Conclusions: BCNU exposure in utero produces histologic alterations suggestive of CD in rat offspring. Dysplastic cortex from this model demonstrates features of hyperexcitability and decreased neuronal sensitivity to GABA. Such physiologic alterations may underlie the increased epileptogenicity of dysplastic cortex.