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Genesis and Migration 3 Genesis and migration 3 Chapter 3 Outline precursor, and it appears that the information to define a given type of cell resides largely in factors derived directly from the What determines the number of cells produced by the precursors. The same is true for the neuroblasts that produce progenitors? 52 the Drosophila central nervous system: the production of neu- rons from the neuroblasts is highly stereotypic. The neuroblasts The generation of neurons and glia 55 of the insect CNS delaminate from the ventral–lateral ecto- Cerebral cortex histogenesis 58 derm neurogenic region in successive waves (see Chapter 1). Cerebellar cortex histogenesis 63 In Drosophila, about 25 neuroblasts delaminate in each seg- ment, and they are organized in four columns and six rows (Doe Molecular mechanisms of neuronal migration 65 and Smouse, 1990). Once the neuroblast segregates from the Postembryonic and adult neurogenesis 67 ectoderm, it undergoes several asymmetric divisions, giving Summary 73 rise to approximately five smaller ganglion mother cells. Each ganglion mother cell then divides to generate a pair of neurons. References 73 These neurons make up the segmental ganglia of the ventral nerve cord and have stereotypic numbers and types of neurons. In the vertebrate, the situation gets considerably more com- The human brain is made up of approximately 100 billion plex. The neural tube of most vertebrates is initially a single neurons and even more glial cells. The sources of all these layer thick. As neurogenesis proceeds, the progenitor cells neurons and glia are the cells of the neural tube, described undergo a large number of cell divisions to produce a much in the previous chapters. Neurogenesis and gliogenesis, the thicker tube. A section through the developing spinal cord is generation of neurons and glia during development, is collec- shown in Figure 3.1A, and an example of a progenitor cell is tively also called histogenesis. Once the neurons and glia are shown as a schematic in Figure 3.1B and in the actual neu- generated by the progenitors during development, they almost ral tube in Figure 3.1C, labeled with a fluorescent protein to always migrate over some distance from their point of ori- visualize the cell as it progresses through a cell division. At gin to their final position. This chapter describes the cellular this stage of development, almost all the cells in the neural and molecular principles by which the appropriate numbers tube resemble those shown in Figure 3.1B,C, with a simple of neurons and glia are generated from the neural precursors, bipolar shape. They extend one process to the central canal and gives an overview of some of the complex cellular migra- of the neural tube (named the ventricular surface because it is tion processes involved in the construction of the brain. The continuous with the ventricles of the brain) and they extend number of cells generated in the developing nervous system their other process to the outer surface of the neural tube. is likely regulated at several levels. In some cases, the pro- If one were just to look at the nuclei of the neural tube at duction of neurons or glia may be regulated by an intrinsic this stage, there would appear to be many cell layers, and at limit in the number of progenitor cell divisions. The level of first, the early neurohistologists thought this was the case. proliferation and ultimately the number of cells generated can However, in the early 1900s it was recognized that the cells of also be controlled by extracellular signals, acting as mitogens, the neural tube move their nuclei from the inside of the neu- promoting progenitor cells to reenter the cell cycle or alterna- ral tube to the outside during each cell cycle. This movement tively as mitotic inhibitors that induce progenitor cells to exit can be directly observed using time lapse recording of cells from the cell cycle. However, as we will see in Chapter 7, the labeled with fluorescent proteins (Figure 3.1C). This constant number of neurons and glia in the mature nervous system is a nuclear movement is termed interkinetic nuclear migration. function not only of cell proliferation, but also of cell death. In this process, the nuclei move to the inner, ventricular sur- As we saw in Chapter 1, the nervous system of C. elegans face moment just before mitosis, and divide into two daugh- (as well as the rest of the animal) is derived from a highly ste- ter cells; then the nuclei of these daughter cells move away reotyped pattern of cell divisions. Therefore, in these animals, from this surface during S-phase; but wherever they are just the lineages of the cells directly predict their numbers. The before the next mitosis, they rapidly move back to the ven- regulation of these cell divisions appears to depend less on inter- tricular surface to complete division (Norden et al., 2009). In actions with surrounding cells than is the case in vertebrates. the developing chick spinal cord, this process can take as little The lineages of the C. elegans progenitor cells also predict the as six hours (Figure 3.1C). Although the function of interki- particular types of neurons that are generated from a particular netic nuclear migration is unknown, it may be necessary for the 49 © 2012 Elsevier Inc. All rights reserved. DEvElOPMENT OF THE NERvOuS SySTEM A B S-phase G2 M-phase G1 S-phase C −3h2 m −28 m −21 m −14 m −7 m0 m7 m 14 m 1h 10 2h 14 3h 17 Fig. 3.1 The neural tube contains the progenitors of all the neurons and glia in the mature brain and spinal cord. A. These progenitors have a simple bipolar morphology. B. The nuclei of the progenitor cells undergo an “in and out” movement (shown here as an “up and down” movement) as they progress through the cell cycle. The cells move to the inside of the neural tube in the G2 phase of the cycle, go through the M-phase at the inner surface (also called the ventricular surface) and then move out again during S-phase. C. An actual time lapse recording showing a fluorescent labeled progenitor in the embryonic chick spinal cord undergo a mitotic division in a little over six hours. The M-phase lasts only about 20 minutes, while the S-phase can last much longer. (A, Courtesy of Kathryn Tosney; B,C, Modified from Wilcock et al., 2007) progenitor cells to receive specific signals at different times in the infection to other cells. This means that only the daugh- the cell cycle. On the other hand, Norden et al. (2009) propose ter cells of the originally infected progenitors will express the that the migration to the ventricular surface prior to the mitotic viral genes. If a retrovirus that contains DNA coding for GFP division may be what is critical, and that the nuclei move away is then injected into the developing brain and infects some of during S-phase to allow other nuclei access to that surface for the proliferating progenitor cells, the progeny of the infected their divisions. They compare this to people at a crowded pub, cells will still express the GFP gene even in adult animals. This jostling around the room most of the time, but quickly returning technique was used in the developing neural tube, and the dis- to the bar for a refill. tribution of clones has been analyzed shortly after injections The cells of the ventricular zone are the precursors of the as well as in the more mature spinal cord (Figure 3.2). When differentiated neurons and glia of the central nervous system. the neural tube was analyzed one day after the retroviral infec- In most other areas of the developing neural tube, once neu- tion, a few progenitors expressed the reporter gene, and their rons and glia are generated by the progenitor cells, the neurons progeny were clustered together, since they had not yet had and glia migrate away from the ventricular surface to continue time to migrate or differentiate; however, if the embryos were their differentiation elsewhere, and much more will be said of allowed to develop several more days to allow the spinal cord this process. Several methods have been developed to track to mature, then the cells that express the reporter gene were the daughter cells of the progenitors once they leave the ven- typically more dispersed.v These cells could be shown to have tricular zone. One of the best ways to track the progeny of a developed from a single progenitor, and are therefore consid- progenitor is using a retrovirus that permanently marks all the ered a “clone” and the technique is sometimes called “clonal daughter cells (Figure 3.2). The retroviral labeling technique analysis.” In the case of the chick spinal cord, many of the takes advantage of the fact that retroviruses will only success- clones contain both motoneurons and glial cells in the white fully infect and integrate their genes into cells that are going matter. In the example shown in Figure 3.2, both astrocytes through the cell cycle. The genome of these viruses can be and oligodendrocytes are derived from the same progenitor modified to contain genes that code for proteins not normally cell that gave rise to the motoneurons (leber et al., 1990). The present in the nervous system but can be detected easily, such clonal analysis method therefore not only allows one to track as green fluorescent protein (GFP). Once the virus infects a the cells as they migrate to other regions of the nervous sys- cell, and the viral genome is integrated into the cell’s DNA, tem, but it also shows that the progenitors can make neurons the viral genes are inherited in all the daughter cells of the and both types of macroglia found in the brain, the astrocytes originally infected cell.
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