Glial Development
4.2 Macroglial cells
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Figure 4.2 Astrocytes of human cortex. Schematic representation of human cortical layers, I to VI. Primate-specific astrocytes are (1) the interlaminar astrocytes, somatas of which reside in Layer I, and processes extend towards layers III and IV, and (2) polarized astrocytes, which are localized in layers V and VI and also send long processes through the cortical layers. Human protoplasmic astrocytes are characterized by a very high complexity of their processes. White matter contains fibrous astrocytes, which are least different from nonprimates. (Modified from Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain.Trends Neurosci29, 547–553)
4.2 MACROGLIAL CELLS 33 these neuroepithelial cells may be defined as true ‘neural progenitors’. These neural progenitors give rise to neuronal or glial precursor cells (‘neuroblasts’ and
‘glioblasts’, respectively), which in turn differentiate into neurones or macroglial cells. For many years it was believed that the neuroblasts and glioblasts appear very early in development, and that they form two distinct and noninterchangeable pools committed, respectively, to produce strictly neuronal or strictly glial lineages. It was also taken more or less for granted that the pool of precursor cells is fully depleted around birth, and neurogenesis is totally absent in the mature brain.
Recently, however, this paradigm has been challenged, as it appears that neuronal and glial lineages are much more closely related than was previously thought, and that the mature brain still has numerous stem cells, which may provide for neuronal replacement. Moreover, it turns out that neural stem cells have many properties of astroglia.
The modern scheme of neural cell development is illustrated in Figure 4.3 and is as follows: At the origin of all neural cell lineages lie neural progenitors
Figure 4.3 Modern views on pathways of neural cell development. Classical theory postulates the very early separation of neural and glial lineages, whereby neural and glial precursors are completely committed to the development of the respective cells (lineage restricted). Recent evidence, however, supports a new hypothesis, in which radial glial cells are multipotent neural precursors, generating neurones and oligodendrocytes, and eventually transforming into astrocytes. Furthermore, radial glia generate a subpopulation of ‘stem’ neural cells that have properties of astrocytes. These ‘stem’ astrocytes underlie adult neurogenesis and can produce either neurones or macroglial cells (see the text for further explanation)
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in the form of neuroepithelial cells. Morphologically, neural progenitors appear as elongated cells extending between the two surfaces (ventricular and pial) of the neuronal tube. Very early in development, the neural progenitors give rise to radial glial cells, which are in fact the first cells that can be distin- guished from neuroepithelial cells. The somatas of radial glial cells are located in the ventricular zoneand their processes extend to the pia. These radial glial cells are the central element in subsequent neurogenesis, because they act as the main neural progenitors during development, giving rise to neurones, astro- cytes, and some oligodendrocytes. The majority of oligodendrocytes, however, originate from glial precursors that are generated in specific sites in the brain and spinal cord (see below). Astrocytes are generated both from radial glia and later in development from glial precursors that also give rise to oligodendro- cytes; the proportion of the final population of astrocytes derived from radial glia and glial precursors depends on the region of the CNS (see below). Radial glia not only produce neurones, but they also form a scaffold along which newborn neurones migrate from the ventricular zone to their final destinations (see Chapter 7). Moreover, the radial glial cells and astrocytes that differentiate from them retain the function of stem cells in the brain throughout maturation and adulthood.
Astrocytes and oligodendrocytes develop from committed glial precursors through several intermediate stages, which have been thoroughly characterized in culture systems, by using several specific antibodies. The first stage in devel- opment of both astrocytes and oligodendrocytes is a bipotential glial precursor, which is probably lineage restricted (originally called theO-2A(oligodendrocyte- type 2 astrocyte) progenitor cell), and can develop into either type of glial cell.
Glial precursors are small cells, with one or more process, and are highly mobile, eventually migrating from multiple sites to colonize the entire CNS white and grey matter. As they migrate, some glial precursors begin to differentiate and acquire markers of astrocytes or OPCs (Figure 4.4). In the forebrain, glial precursors in the subventricular zone migrate into both white matter and cortex, to become astrocytes, oligodendrocytes and NG2-glia (as well as some interneurones). In the cerebellum, some Bergmann glia and other astrocytes arise from radial glia (and some share a common lineage with Purkinje neurones), and later in development glial progenitors migrate from an area dorsal to the IVth ventricle to give rise to all types of cerebellar astrocytes, myelinating oligodendrocytes and NG2-glia (as well as interneurones). In the embryonic retina, common precursors give rise to both neurones and Müller glia; glial precursors that migrate into the retina via the optic nerve give rise to astrocytes, but oligodendrocytes and NG2-glia are absent from the retina of most species. Astrocytes and oligodendrocytes in the spinal cord appear to arise from different precursors in separate areas of the ventricular zone.
The ventral neuroepithelium of the embryonic cord is divided into a number of domains, which contain precursors that first generate neurones (motor neurones and interneurones) and then oligodendrocytes. Astrocytes most likely arise from radial glia.