Nonmyelinating Schwann Cells

Glial Development

4.1 Phylogeny of glia and evolutionary specificity of glial cells in human brain

Glia appear early in phylogeny; even primitive nervous systems of invertebrates such as annelids and leeches, crustacea and insects, and molluscs and cephalopods contain clearly identifiable glial cells, and their study has provided a significant contribution to our understanding of glial cell physiology. Most strikingly, however, the evolution of the CNS is associated with a remarkable increase in the number and complexity of glial cells (Figure 4.1). In the leech, for example, the nervous system is organized in ganglia; each ganglion contains 20-30 neurones, which are coupled to one giant (up to 1 mm in diameter) glial cell. The nervous system of the nematode Caenorhabditis elegans contains 302 neurones and only 56 glial cells (i.e. glia account for about 16 per cent of all neural cells). In drosophila, glial cells already account for ~20-25 per cent of cells in the nervous system, and in rodents about 60 per cent of all neural cells are glia.

In human brain, glial cells are certainly the most numerous as it is generally believed that glial cells outnumber neurones in human brain by a factor of 10 to 50; although the precise number of cells in the brain of Homo sapiens remains unknown. Early estimates put a total number of neurones at ~85 billion; however, now we know that this number should be substantially larger as a cerebellum alone contains ~105 billion neurones. Therefore, the human brain as a whole may contain several hundred billions of neurones and probably several trillions (or thousand billions) of astrocytes. Morphological data for the cortex are more reliable and they show that human brain has the highest glia to neurone ratio among all species (this ratio is 0.3:1 in mice and about 1.65:1 in human brain - see Figure 4.1). Interestingly, however, the overall volume of the glial compartment remains more or less constant as they occupy about 50 per cent of the nervous system throughout the evolutionary ladder.

Not only does the human brain have the largest number of glia, but the glial cells in primates also show remarkable differences compared to nonprimates. The

Schwann Cells

Figure 4.1 Phylogenetical advance of glial cells:

A. Percentage of glial cells is increased in phylogenesis. In fact the total quantity of neural cells in the brain of higher primates, including Homo sapiens, is not known precisely; the number of neurones in human brain can be as high as several hundred of billions. It is commonly assumed that glia outnumber neurones in human brain by a factor of 10 to 50 (e.g. Kandel, Nerve cells and behaviour. In: Principles of neural science, Kandel ER, Schwartz JH, Jessell TM, Eds, 4th edition, pp. 19-35. New York: McGraw-Hill) although the precise ratio remains to be determined.

B. The numbers of glia and neurones in cortex is more precisely quantified, and this graph shows the glia/neurone ratio in cortex of high primates; this ratio is the highest in humans. (Data are taken from Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI, Goodman M, Redmond JC, Bonar CJ, Erwin JM, Hof PR (2006) Evolution of increased glia-neuron ratios in the human frontal cortex. Proc Natl Acad Sci USA 103, 13606-13611).

C. Graphic representation of neurones and astroglia in mouse and in human cortex. Evolution has resulted in dramatic changes in astrocytic dimensions and complexity.

D. Relative increase in glial dimensions and complexity during evolution. Linear dimensions of human astrocytes when compared with mice are ~2.75 times larger; and their volume is 27 times larger; human astrocytes have ~10 times more processes and every astrocyte in human cortex enwraps ~20 times more synapses.

(C, D - adapted from Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29, 547-553)

most abundant astroglial cell in human and primate brain are the protoplasmic astrocytes, which densely populate cortex and hippocampus. Human protoplasmic astrocytes are much larger and far more complex than protoplasmic astrocytes in rodent brain. The linear dimensions of human protoplasmic astroglial cells are about 2.75 times larger and have a volume about 27 times greater than the same cells in mouse brain. Furthermore, human protoplasmic astrocytes have about 40 main processes and these processes have immensely more complex branching than mouse astrocytes (which bear only 3-4 main processes). As a result, every human protoplasmic astrocyte contacts and enwraps ~ two million synapses compared to only 90 000 synapses covered by the processes of a mouse astrocyte.

Moreover, the brain of primates contains specific astroglial cells, which are absent in other vertebrates (Figure 4.2). Most notable of these are the interlaminar astrocytes, which reside in layer I of the cortex; this layer is densely populated by synapses but almost completely devoid of neuronal cell bodies. These interlaminar astrocytes have a small cell body (~10 ^m), several short and one or two very long processes; the latter penetrate through the cortex, and end in layers III and IV; these processes can be up to 1 mm long. The endings of the long processes create a rather unusual terminal structure, known as the 'terminal mass' or 'end bulb', which are composed of multilaminal structures, containing mitochondria. Most amazingly, the processes of interlaminar astrocytes and size of 'terminal masses' were particularly large in the brain of Albert Einstein; although whether these features were responsible for his genius is not really proven. The function of these interlaminar astrocytes remain completely unknown, although it has been speculated that they are the astroglial counterpart of neuronal columns, which are the functional units of the cortex, and may be responsible for a long-distance signalling and integration within cortical columns. Quite interestingly, interlaminar astrocytes are altered in Down syndrome and Alzheimer's disease.

Human brain also contains polarized astrocytes, which are uni- or bipolar cells which dwell in layers V and VI of the cortex, quite near to the white matter; they have one or two very long (up to 1 mm) processes that terminate in the neuropil. The processes of these cells are thin (2-3 ^m in diameter) and straight; they also have numerous varicosities. Once more, the function of polarized astrocytes remains enigmatic; although they might be involved in para-neuronal long-distance signalling.

Most interestingly, the evolution of neurones produced fewer changes in their appearance. That is, the density of synaptic contacts in rodents and primates is very similar (in rodent brain the mean density of synaptic contacts is ~1397 millions/mm3, which is not very much different from humans - synaptic density in human cortex is around 1100 millions/mm3). Similarly, the number of synapses per neurone does not differ significantly between primates and rodents. The shape and dimensions of neurones also has not changed dramatically over the phylogenetic ladder: human neurones are certainly larger, yet their linear dimensions are only ~1.5 times greater than in rodents.

Thus, at least morphologically, evolution resulted in far greater changes in glia than in neurones, which most likely has important, although yet undetermined, significance.

Cortical Layers

Cell Layers Human Cortex

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 Neurosci 29, 547-553)

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 Neurosci 29, 547-553)

4.2 Macroglial cells

All neural cells (i.e. neurones and macroglia) derive from the neuroepithelium, which forms the neural tube. These cells are pluripotent in a sense that their progeny may differentiate into neurones or macroglial cells with equal probability, and therefore 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

Schwann Cell

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)

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)

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 distinguished from neuroepithelial cells. The somatas of radial glial cells are located in the ventricular zone and 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 development of both astrocytes and oligodendrocytes is a bipotential glial precursor, which is probably lineage restricted (originally called the O-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.

Oligodendroglial lineage

Schwann Cells

Figure 4.4 Oligodendroglial lineage. Oligodendrocyte precursor cells (OPCs), in culture at least, can generate oligodendrocytes or astrocytes (O-2A cell), although in vivo they may only generate oligodendrocytes. OPCs are characterized by expression of platelet-derived growth factor alpha receptors (PDGFaR), the NG2 chondroitin sulphate proteoglycan (SPG), and the ganglioside GD3; these play important roles in proliferation and migration of OPCs. OPCs are generated in localized sources in the brain and spinal cord from which they migrate to their final locations throughout the CNS. There, oligodendrocyte precursors transform into fully committed immature oligodendrocytes, characterized by expression of the O4 antigen. These O4-positive cells further differentiate into mature oligodendrocytes, expressing galactocerebroside (GC) and producing myelin. Under appropriate culture conditions, OPCs spontaneously transform into oligodendrocytes in the absence of axons, but in vivo oligodendrocyte proliferation, survival, differentiation and myelination are regulated by axonal signals

Figure 4.4 Oligodendroglial lineage. Oligodendrocyte precursor cells (OPCs), in culture at least, can generate oligodendrocytes or astrocytes (O-2A cell), although in vivo they may only generate oligodendrocytes. OPCs are characterized by expression of platelet-derived growth factor alpha receptors (PDGFaR), the NG2 chondroitin sulphate proteoglycan (SPG), and the ganglioside GD3; these play important roles in proliferation and migration of OPCs. OPCs are generated in localized sources in the brain and spinal cord from which they migrate to their final locations throughout the CNS. There, oligodendrocyte precursors transform into fully committed immature oligodendrocytes, characterized by expression of the O4 antigen. These O4-positive cells further differentiate into mature oligodendrocytes, expressing galactocerebroside (GC) and producing myelin. Under appropriate culture conditions, OPCs spontaneously transform into oligodendrocytes in the absence of axons, but in vivo oligodendrocyte proliferation, survival, differentiation and myelination are regulated by axonal signals

4.3 Astroglial cells are brain stem cells

Neurogenesis in the mammalian brain occurs throughout the lifespan. New neurones that continuously appear in the adult brain are added to neural circuits, and may even be responsible for the considerable plasticity of the latter. The appearance of new neurones does not happen in all brain regions of mammals; it is mainly restricted to hippocampus and olfactory bulb (although in nonmammalian vertebrates neurogenesis occurs in almost every brain region).

In both hippocampus (in its subgranular zone) and in the subventricular zone (the latter produces neurones for the olfactory bulb) the stem cells have been identified as astrocytes. It remains unclear whether astroglial cells in other brain regions may also retain these stem cell capabilities.

4.4 Schwann cell lineage

The Schwann cell lineage (Figure 4.5) starts from Schwann cell precursors, which in turn, are the progeny of neural crest cells, which also give rise to peripheral sensory and autonomic neurones and satellite cells of the dorsal root ganglia. By around the time of birth, Schwann cell precursors have developed into immature Schwann cells, and the latter differentiate into all four types of mature Schwann cells. An important juncture in the progression of the Schwann cell lineage occurs when some of the immature cells establish contacts with large-diameter axons and commence the process of myelination (see also Chapter 8). Immature Schwann cells that happen to associate with small diameter axons remain nonmyelinating. An important difference between nonmyelinating and myelinating Schwann cells is that the former maintain contacts with several thin axons, whereas myelinating Schwann cells always envelop a single axon of large diameter.

Schwann cell precursors and immature Schwann cells are capable of frequent division, and proliferation stops only when cells arrive at their terminal differentiation stage. However, mature Schwann cells (both myelinating and nonmyelinating) can swiftly dedifferentiate and return into the proliferating stage similar to immature cells. This dedifferentiation process underlies the Wallerian degeneration that

Microglial Differentiation

Figure 4.5 Schwann cell lineage. Schwann cell precursors appear from neuroepithelial cells, and differentiate into immature Schwann cells. The latter can further differentiate into either nonmyelinating Schwann cells, or after contacting the axon, transform into pro-myelinating Schwann cells and then myelinating Schwann cells. The differentiation and fate of Schwann cells are under the tight control of axonal signals

Figure 4.5 Schwann cell lineage. Schwann cell precursors appear from neuroepithelial cells, and differentiate into immature Schwann cells. The latter can further differentiate into either nonmyelinating Schwann cells, or after contacting the axon, transform into pro-myelinating Schwann cells and then myelinating Schwann cells. The differentiation and fate of Schwann cells are under the tight control of axonal signals follows injury of peripheral nerves (see Chapters 9 and 10). After completion of nerve regeneration, Schwann cells once more redifferentiate.

4.5 Microglial cell lineage

Microglial cells derive from the myelomonocytic lineage, which in turn develops from hemangioblastic mesoderm. The progenitors of microglial cells, known as foetal macrophages (Figure 4.6) enter the neural tube at early embryonic stages (e.g. at embryonic day 8 in rodents). These foetal macrophages are tiny rounded cells and in the course of development they transform into embryonic microglia

Embryonic neuroepithelium

Perinatal brain Amoeboid microglia in corpus callosum

Perinatal brain Amoeboid microglia in corpus callosum

Amoeboid Microglia

Figure 4.6 Ontogenetic development of microglia. The ontogenetic development of microglia comprises three developmental stages. Foetal macrophages are identified in the neuroepithelium at a very early stage (~8 embryonic day in rodents). In perinatal brain, macrophages invade corpus callosum and form clusters of amoeboid microglia. These amoeboid microglial cells migrate into the brain and transform into ramified, resting microglia. (From W.J. Streit, 'Microglial cells'; In: Neuroglia, H. Kettenmann and B.R. Ransom, Eds, 2005, p. 61 by permission of Oxford University Press)

Figure 4.6 Ontogenetic development of microglia. The ontogenetic development of microglia comprises three developmental stages. Foetal macrophages are identified in the neuroepithelium at a very early stage (~8 embryonic day in rodents). In perinatal brain, macrophages invade corpus callosum and form clusters of amoeboid microglia. These amoeboid microglial cells migrate into the brain and transform into ramified, resting microglia. (From W.J. Streit, 'Microglial cells'; In: Neuroglia, H. Kettenmann and B.R. Ransom, Eds, 2005, p. 61 by permission of Oxford University Press)

that have a small cell body and several short processes. In the perinatal period, some of microglial precursors turn into amoeboid microglia, dense clusters of which appear in the corpus callosum. Del Rio Hortega called these groups of rapidly dividing glial precursors fountains of microglia, which persist in the corpus callosum for about two weeks after birth (Figure 4.6). The amoeboid microglial cells proliferate very rapidly and migrate into the cortex, where they settle and turn into ramified resting microglia. Microglia play an essential phagocytic role during development, removing the debris that arises from the large degree of neural apoptosis during development. Microglia can be 'killers' as well as 'cleaners' in the developing CNS; for example, in the embryonic retina, immature neurones express receptors for nerve growth factor (NGF) and these are down-regulated as neurones mature, but excess neurones do not lose their receptors and die by apoptosis in response to NGF released by microglia. Microglia are also responsible for immune tolerance to CNS antigens, by migrating into the embryonic CNS and providing a memory of 'self' before the blood-brain barrier is formed, after which the CNS becomes immune privileged and largely isolated from the systemic immune system. Amoeboid microglia in the developing CNS express many antigenic markers in common with systemic macrophages, but these are down-regulated as they differentiate into resting microglia. Any insult to the CNS results in the activation of microglia, which regain an amoeboid morphology, macrophage antigens and a phagocytic function.

Microglial cells retain their mitotic capabilities and they continue to divide (albeit at a very slow rate) in the adult. An additional source of microglial cells in the mature brain are so-called perivascular mononuclear phagocytes. These cells provide for immune surveillance in the CNS, crossing the blood-brain barrier and passing through the brain parenchyma and along the perivascular spaces, into the subarachnoid space and thence into the lymphatics. These cells may enter the brain tissue and become transformed into resting microglial cells. Following insults to the adult CNS, macrophages may again enter the brain and are often indistinguishable from resident activated microglia - in these cases, most studies do not distinguish between microglia and macrophages (generally identified antigenically), and the terms are used interchangeably.

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