The mammalian telencephalon, which comprises the cerebral cortex, olfactory bulb, hippocampus, basal ganglia, and amygdala, is the most complex and intricate region of the CNS. It is the seat of all higher brain functions including the storage and retrieval of memories, the integration and processing of sensory and motor information, and the regulation of emotion and drive states. In higher mammals such as humans, the telencephalon also governs our creative impulses, ability to make rational decisions, and plan for the future. Despite its massive complexity, exciting work from a number of groups has begun to unravel the developmental mechanisms for the generation of the diverse neural cell types that form the circuitry of the mature telencephalon. Here, we review our current understanding of four aspects of neural development. We first begin by providing a general overview of the broad developmental mechanisms underlying the generation of neuronal and glial cell diversity in the telencephalon during embryonic development. We then focus on development of the cerebral cortex, the most complex and evolved region of the brain. We review the current state of understanding of progenitor cell diversity within the cortical ventricular zone and then describe how lateral signaling via the Notch‐Delta pathway generates specific aspects of neural cell diversity in cortical progenitor pools. Finally, we review the signaling mechanisms required for development, and response to injury, of a specialized group of cortical stem cells, the radial glia, which act both as precursors and as migratory scaffolds for newly generated neurons.

We used several animal models to study global and regional cortical surface expansion: The lissencephalic mouse, gyrencephalic normal ferrets, in which the parietal cortex expands more than the temporal cortex, and moderately lissencephalic ferrets, showing a similar degree of temporal and parietal expansion. We found that overall cortical surface expansion is achieved when specific events occur prior to surpragranular layer formation. (1) The subventricular zone (SVZ) shows substantial growth, (2) the inner SVZ contains an increased number of outer radial glia and intermediate progenitor cells expressing Pax6, and (3) the outer SVZ contains a progenitor cell composition similar to the combined VZ and inner SVZ. A greater parietal expansion is also achieved by eliminating the latero-dorsal neurogenic gradient, so that neurogenesis displays a similar developmental degree between parietal and temporal regions. In contrast, mice or lissencephalic ferrets show more advanced neurogenesis in the temporal region. In conclusion, we propose that global and regional cortical surface expansion rely on similar strategies consisting in altering the timing of neurogenic events prior to the surpragranular layer formation, so that more progenitor cells, and ultimately more neurons, are produced. This hypothesis is supported by findings from a ferret model of lissencephaly obtained by transiently blocking neurogenesis during the formation of layer IV.

During cerebral cortical development, g-aminobutyric acidergic (GABAergic) interneurons arise from a different site than projection neurons. GABAergic cells are generated in the subpallial ganglionic eminence (GE), while excitatory projection neurons arise from the neocortical ventricular zone. Our laboratory studies a model of cortical dysplasia that displays specific disruption of GABAergic mechanisms and an alteration in the overall balance of excitation in the neocortex. To produce this model, the birth of neurons on a specific gestational day in ferrets (embryonic day 33 [E33]) is interrupted by injection of the antimitotic methylazoxymethanol (MAM). We hypothesized that migration of interneurons might be disrupted in this cortical dysplasia paradigm. We observed that although interneurons migrate into the neocortex in both normal and dysplastic cortex, the migrating cells become disoriented over time after E33 MAM treatment. Coculture experiments using normal GE and MAM-treated cortex (and vice versa) demonstrate that cues dictating proper orientation of migrating interneurons arise from the cortex and are not intrinsic to the migrating cells. As a consequence, interneurons in mature brains of MAM-treated animals are abnormally distributed. We report that GABA A receptor activation is crucial to the proper positioning of interneurons migrating into the cortex from the GE in normal and MAM-treated animals.

The relationship between radial glia and neurons migrating tangentially from the ganglionic eminence (GE) has been suggested but not firmly established. To study this relationship we used a ferret model of cortical dysplasia where radial glia are highly disorganized. To produce this, an antimitotic, methylazoxy methanol (MAM) is injected on the 24th day of gestation (E24 MAM). Neurons migrating away from the GE in MAM-treated animals tend to remain in the intermediate zone (IZ) and do not reach the cortical plate (CP) as they do in normal ferret slices. We recently observed that the disrupted radial glia after MAM treatment could be restored toward their normal morphology by exogenous application of neuregulin1 (NRG1). We demonstrate here that when E24 MAM slices are treated with NRG1, the distribution of cells arising from the GE was similar to normal slices. In a second paradigm, we disrupted radial glia by adding ciliary neurotrophic factor (CNTF) to the culture media of normal ferret slices; CNTF induces acute differentiation of radial glia into astrocytes. After CNTF exposure, few tangentially migrating cells reach the CP compared to untreated slices. These results show that interneurons fail to reach the CP by disrupted normal radial glia and restoring the normal radial glial scaffold is sufficient to allow migrating cells to invade the CP. Our results suggest an important role for radial glia by controlling directly or indirectly the migration of interneurons to the CP, their main target.