Cerebral Cortex Histogenesis

In the next section, the histogenesis of two specific regions of the CNS—the cerebral cortex and the cerebellum—will be highlighted; histogenesis of these structures has been the subject of intense study for many years. As noted in the previous chapter, the cerebral hemispheres develop from the wall of the telen-cephalic vesicle. The neuroepithelial cells initially span the thickness of the wall, and as they continue to undergo cell division, the area of the hemispheres expands. At this early stage of development, the progenitor cells are thought to undergo primarily symmetric cell divisions, and their progeny both remain in the cell cycle. Soon, however, a few cells withdraw from the cycle to develop as the first cortical neurons. These neurons migrate a short distance to form a distinct layer, just beneath the pial surface, known as the preplate (Figure 3.15). The preplate consists of two dis tinct cell types: a more superficial marginal zone, containing a group of large, stellate-shaped cells, known as Cajal-Retzius cells, and a deeper zone of cells called the subplate cells (Marin-Padilla, 1988; Allendoerfer and Shatz, 1994). The next stage of cortical development is characterized by a large accumulation of newly postmitotic neurons within the preplate (Marin-Padilla, 1988). These new neurons form the cortical plate. The cortical plate divides the preplate into the superficial marginal zone, composed primarily of the Cajal-Retzius cells, and the intermediate zone, composed of the subplate cells and increasing numbers of incoming axons. The developing cortex is thus described as having four layers: the ventricular zone, the intermediate zone, the cortical plate, and the marginal zone.

At the very earliest stages of cortical development, the processes of the progenitor cells span the entire thickness of the cortex. The first cortical neurons that are generated use the predominantly radial orientation of their neighboring progenitor cells to guide their

Cajal Retzius Cells Marginal Zone

FIGURE 3.15 Histogenesis in the cerebral cortex proceeds through three stages. In the first stage of histo-genesis, the wall of the cerebral cortex is made up of the progenitor cells, which occupy the ventricular zone (VZ). In the next stage of development, the first neurons exit the cell cycle (red) and accumulate in the preplate, adjacent to the pial surface. The neurons of the preplate can be divided into the more superficial Cajal-Retzius cells and the subplate cells. In the next stage of cortical histogenesis, newly generated neurons (red) migrate along radial glial fibers to form a layer between the Cajal-Retzius cells and the subplate. This layer is called the cortical plate, and the majority of the neurons in the cerebral cortex accumulate in this layer.

FIGURE 3.15 Histogenesis in the cerebral cortex proceeds through three stages. In the first stage of histo-genesis, the wall of the cerebral cortex is made up of the progenitor cells, which occupy the ventricular zone (VZ). In the next stage of development, the first neurons exit the cell cycle (red) and accumulate in the preplate, adjacent to the pial surface. The neurons of the preplate can be divided into the more superficial Cajal-Retzius cells and the subplate cells. In the next stage of cortical histogenesis, newly generated neurons (red) migrate along radial glial fibers to form a layer between the Cajal-Retzius cells and the subplate. This layer is called the cortical plate, and the majority of the neurons in the cerebral cortex accumulate in this layer.

migration. However, the accumulation of neurons within the cortical plate results in a marked increase in cortical thickness. As a result, the processes of progenitor cells no longer are able to extend to the external surface of the cortex. Nevertheless, the newly generated cortical neurons still migrate primarily in a radial direction. How is this accomplished? To guide the newly generated cortical neurons to their destinations, a remarkable set of cells, known as radial glia, provide a scaffold. These glial cells have long processes that extend from the ventricular zone all the way to the pial surface. They form a scaffold that neurons migrate along. Serial section electron microscopic studies by Pasko Rakic first clearly demonstrated the close association of migrating neurons with the radial glial cells in the cerebral cortex (Figure 3.16). The migrating neurons wrap around the radial glial processes like a person climbing a pole. In recent years, it has been possible to directly observe the process of neuronal migration in vitro using dissociated cell cultures (Edmonson and Hatten, 1987) or cortical slices (O'Rourke et al., 1995). These studies have confirmed that newly generated neurons migrate along the glial cells and that the process is saltatory, with migrating neurons frequently starting and stopping along the way.

The next phase of cortical histogenesis is characterized by the gradual appearance of defined layers within the cortical plate. As increasing numbers of newly generated neurons migrate from the ventricular zone into the cortical plate, they settle in progressively more peripheral zones. Meanwhile, the earlier-generated neurons are differentiating. Thus, later-generated neurons migrate past those generated earlier. This results in an inside-out development of cortical layers (Figure 3.17). Richard Sidman (Angevine and Sidman, 1961) used the 3H-thymidine birthdating technique

Radial Glial Migration Cortex

FIGURE 3.16 Migration of neurons along radial glia. The radial glial fibers extend from the ventricular zone to the pial surface of the cerebral cortex. A section through the cerebral cortex at an intermediate stage of histogenesis shows the relationship of the radial glia and the migrating neurons. The postmitotic neurons wrap around the radial glia on their migration from the ventricular zone to their settling point in the cortical plate. (Modified from Rakic, 1972)

FIGURE 3.16 Migration of neurons along radial glia. The radial glial fibers extend from the ventricular zone to the pial surface of the cerebral cortex. A section through the cerebral cortex at an intermediate stage of histogenesis shows the relationship of the radial glia and the migrating neurons. The postmitotic neurons wrap around the radial glia on their migration from the ventricular zone to their settling point in the cortical plate. (Modified from Rakic, 1972)

described above to first demonstrate the inside-out pattern of cerebral cortical histogenesis. The neurons labeled in the cortex of pups born from pregnant female rats injected with thymidine on the 13th day of gestation were located in the deeper layers of cortex, whereas the neurons labeled after a thymidine injection on the 15th day of gestation were found more superficially (Figure 3.17). This inside-out pattern of cortical neurogenesis is conserved across mammalian species. Figure 3.18 shows the results of similar thymi-dine birthdating experiments in the monkey, where the process of neurogenesis is much more prolonged than in the rat. Thymidine injections at progressively later stages of gestation result in progressively more superficial layers of cerebral cortical neurons being labeled. Each cortical layer has a relatively restricted period of developmental time over which it is normally generated (Figure 3.18).

While the crawling of the neuroblast along the radial glial scaffold has been well recognized for over 30 years, recent direct visualization of the process in developing mouse cerebral cortex has yielded some surprises. In these studies, the ventricular zone was labeled using a dye that marked a subpopulation of the newly generated neuroblasts. As these cells left the ventricular zone, their leading processes were visible. Time-lapse imaging of dye-labeled neuroblasts shows clearly that many of the neuroblasts migrate just as predicted from the EM reconstructions of Rakic. However, direct visualization of the migration process also revealed that many of the neuroblasts move via a very different process, a process termed somal translocation.

Birth | | |

Process tissue

Process tissue

FIGURE 3.17 Birth da ting studies demonstrate the inside-out pattern of cerebral cortical histogenesis. Pregnant female rats are given injections of 3H-thymidine at progressively later stages of gestation. When the pups are born, they are allowed to survive to maturity, and then their brains are processed to reveal the labeled cells. Neurons that have become postmitotic on embryonic day 11 are found primarily in the subplate (now in the subcortical white matter), while neurons "born" on day E13 are found in deep cortical layers, that is, V and VI, and neurons generated on E15 are found in more superficial cortical layers, that is, IV, III, and II. The most superficial layer, layer I, contains only the remnants of the preplate neurons (not shown). (Modified from Angevine and Sidman, 1961)

FIGURE 3.17 Birth da ting studies demonstrate the inside-out pattern of cerebral cortical histogenesis. Pregnant female rats are given injections of 3H-thymidine at progressively later stages of gestation. When the pups are born, they are allowed to survive to maturity, and then their brains are processed to reveal the labeled cells. Neurons that have become postmitotic on embryonic day 11 are found primarily in the subplate (now in the subcortical white matter), while neurons "born" on day E13 are found in deep cortical layers, that is, V and VI, and neurons generated on E15 are found in more superficial cortical layers, that is, IV, III, and II. The most superficial layer, layer I, contains only the remnants of the preplate neurons (not shown). (Modified from Angevine and Sidman, 1961)

The migrating cell has a leading process that extends to the pial surface, while the cell body is still near the ventricular zone at this early stage of cerebral cortical development. Then, as the process gets progressively shorter, it draws the cell soma to the pial layer as if it were doing pull-ups on a bar (Nadarajah et al., 2001). At the same time, other neuroblasts are migrating with relatively constant leading processes, and presumably these are more like those described from the EM reconstructions. Some neuroblasts show both modes of migration at different points in their path.

The direct visualization of neuronal migration gave rise to another surprise. The relationship between the radial glia and the progenitor cells has long been thought to be separate. The glia were thought to be

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