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Macroglial Lineages
Macroglial Lineages 597
Macroglial Lineages A M Butt, University of Portsmouth, Portsmouth, UK
Neuroepithelium
ã 2009 Published by Elsevier Ltd.
Neurons and macroglia derive from the neuroepithelium, which at the earliest stages of development forms the neural plate. As the neural plate thickens, the neural groove forms and the neural plate closes dorsally to form the neural tube, the lumen of which becomes the ventricular system. The cells lining the ventricles of the neural tube form a primary proliferative zone termed the ventricular zone (VZ), and a secondary proliferative zone called the subventricular zone (SVZ) emerges later from the VZ. The VZ ultimately disappears, but the SFV persists into adulthood within the forebrain. As the neural tube expands, the rostral area delineates into the forebrain, midbrain, and hindbrain, and the caudal neural tube forms the spinal cord. During this regionalization, neural crest cells differentiate from the neural tube and migrate to specific regions to form the neurons and glia of the PNS. Thus, CNS and PNS neural cells have clearly distinct lineages from an early stage.
Introduction Macroglia together with neurons make up the two classes of neural cells in the central nervous system (CNS); both macroglia and neurons have a common neuroectodermal embryonic origin. The three major subtypes of macroglia are astrocytes, oligodendrocytes, and the ependymal cells. The fourth major glial cell type in the CNS is the microglia, which are nonneuronal cells that have a mesodermal origin; microglia originate from macrophages that invade the brain during early development. There are also many glia in the peripheral nervous system (PNS), mainly Schwann cells, together with satellite cells of sensory and sympathetic ganglia and glial cells of the enteric nervous system of the gastrointestinal tract. CNS and PNS neural cells have clearly distinct lineages from an early stage of embryonic development. Astroglia and oligodendroglia are the most numerous and functionally important macroglial cell types; ependymal cells are simple cuboidal cells that line the ventricles in the brain and the central canal in the spinal cord. Astrocytes are morphologically and functionally diverse and have a widespread distribution throughout the brain and spinal cord; astrocytes have the archetypal feature of expressing glial fibrillary acidic protein (GFAP). The two major classes of astrocytes are protoplasmic astrocytes and fibrous astrocytes, which are found in the gray and white matter, respectively. In addition, there are specialized astroglial cells throughout the CNS; for example, radial glia are bipolar astroglial cells that predominate in the developing brain, and Mu¨ller glia and Bergmann glia are specialized astroglia restricted to the retina and cerebellum, respectively. Unlike astroglia, oligodendroglia are highly specialized cells and consequently have a more restricted distribution; oligodendrocytes form the myelin sheaths that insulate axons in the CNS and are most numerous in white matter. Until recently, the accepted model was that macroglia and neurons were derived from separate glial and neural progenitors. However, glial and neuronal lineages are much more closely related than was previously thought. Astrocytes and oligodendrocytes develop from multipotent neural stem cells that also generate neurons. Indeed, astroglial stem cells and oligodendrocyte progenitor cells (OPCs) persist in the mature brain and are potential sources of new neurons in the adult.
Radial Glia Are Neural Stem Cells The neuroepithelial cells of the VZ can be considered multipotent neural stem cells in the sense that their progeny gives rise to all of the neurons and macroglia in the CNS. The first cells that emerge from the neuroepithelium are the radial glia. These are distinguished from neuroepithelial cells by the expression of a number of antigens, including the astroglial markers GFAP, vimentin, and the calcium-binding protein S-100b, as well as the glutamate transporter GLAST, nestin, and tenascin-C. The somatas of radial glial cells are located in the VZ and their processes extend to the opposite wall of the neural tube or the pial surface. Radial glia are the main neural stem cells during development and are responsible for most of the subsequent neurogenesis, giving rise first to neurons and later to astrocytes and some oligodendrocytes by a process of ‘transdifferentiation.’ The majority of oligodendrocytes, however, originate at an early stage of development from glial precursors that are generated in specific sites in the brain and spinal cord. Astrocytes are generated later in development, both from radial glia and from glial precursors that also give rise to oligodendrocytes; the proportion of the final population of astrocytes derived from radial glia and glial precursors depends on the region of the CNS. Radial glia not only produce neurons and glia but also form a scaffold along which newborn progenitors migrate from the SVZ. Moreover, the radial glial cells and astrocytes that differentiate from them retain the function of stem cells in the adult brain.
598 Macroglial Lineages
Glial Restricted Precursors Multipotent neural stem cells (neuroepithelium) do not differentiate into astrocytes and oligodendrocytes directly but, rather, through intermediate lineage-restricted stages. The first of these to develop are the glial-restricted precursors, which are distinguished from neuroepithelial cells by expression of A2B5 and nestin and are localized to the ventral neural tube. Several stages in the development of astrocytes and oligodendrocytes have been distinguished, with the main ones being oligodendrocyte and type2 astrocyte precursors (O2A cells), oligodendrocyte precursors, astrocyte precursors, and NG2-expressing glia. The first stage in the differentiation of oligodendrocytes and probably astrocytes is the bipotential O2A glial precursor, which in vitro can generate either type of glial cell; O2A cells are distinguished by expression of platelet-derived growth factor-a receptors (PDGF-aRs) and NG2, in addition to A2B5. It is uncertain to what extent O2A cells are bipotential in vivo, where they may serve predominantly as OPCs which generate only oligodendrocytes. OPCs express the early oligodendrocyte lineage markers PDGF-aR and NG2 and later the homeobox transcription factor Nkx2.2 and the oligodendrocyte lineage gene Olig2 (basic helix–loop–helix factor). Astrocyte precursors have been isolated from numerous regions of the embryonic CNS; they express A2B5 but not GFAP until a relatively late stage of differentiation, and they are therefore difficult to distinguish from glial precursors and O2A cells. Expression of the extracellular matrix transmembrane protein CD44 may serve as an astrocyte precursor marker. Early glial precursors are small cells, with one or more processes, and are highly mobile, migrating from multiple sites to colonize the entire CNS white and gray matter. They do not express early glial antigens such as PDGF-aR and NG2 until they exit the SVZ, and as they migrate, they begin to acquire markers of OPCs and astrocytes. The relative contributions of O2A cells, OPCs, and astrocyte precursors to gliogenesis in vivo are not clear; they display many similarities and may represent different stages in glial precursor differentiation or distinct lineages that arise separately from neural precursors. Indeed, at least in vitro, glial precursors are not truly lineage restricted in that they can generate neurons, astrocytes, and oligodendrocytes under appropriate culture conditions. In addition, after generating oligodendrocytes during development, a significant population of NG2 glia persists throughout the white and gray matter of the adult brain; the functions of adult NG2 glia are unresolved, but they serve in part as a pool of adult OPCs and they may even be multipotent adult neural stem cells. There are
also GFAP-positive astrocyte-like neural stem cells in specific regions of the adult CNS, and these are multipotent and self-renewing.
Regional Variations In the forebrain, glial precursors in the SVZ migrate along radial glia to their final sites in the white matter and cortex to generate oligodendrocytes and some astrocytes, in addition to adult NG2 glia. Astrocytes are derived from migratory glial precursors and from radial glia. In early forebrain development, oligodendrocyte precursors are generated in localized sites ventrally and migrate dorsally. Later, glial precursors that originate from a large dorsolateral SVZ near the lateral ventricle give rise to oligodendrocytes and some astrocytes. Oligodendrocytes and the diverse astrocyte cell types in the cerebellum are derived predominantly from migratory glial precursors from an area dorsal to the fourth ventricle; Bergmann glia arise from embryonic radial glia and share a common lineage with Purkinje neurons. In the embryonic retina, Muller glia arise from a common precursor with neurons, and astrocytes develop at a later stage from glial precursors that migrate into the retina via the optic nerve; oligodendrocytes are absent from the retina of most species. Most astrocytes in the optic nerve are derived from intrinsic radial-like astroglia, whereas oligodendrocyte precursors migrate into the nerve during the perinatal period. In the spinal cord, oligodendrocytes originate from neural stem cells in the ventral neuroepithelium, which first generate neurons and then oligodendrocyte precursors. Later, oligodendrocyte precursors also originate from dorsal areas. Spinal cord astrocytes appear to be derived from separate astrocyte precursors after neurons and oligodendrocytes; as in other areas of the CNS, astrocytes most likely also arise from radial glia.
Gliogenesis in the Adult Central Nervous System Gliogenesis occurs at a slow rate throughout the adult CNS. New glial cells are born locally, predominantly from parenchymal multipotent glial precursor cells and also, in the case of astrocytes, from division of mature cells. The type of cell produced is determined by locality of the precursors; they mostly produce oligodendrocytes in white matter, whereas astrocytes and oligodendrocytes are produced in the same quantities elsewhere. These glial precursors do not express GFAP, but they do express nestin and NG2. It is not clear that all NG2-expressing glia in the adult CNS are glial precursors. NG2 glia are slowly proliferating
Macroglial Lineages 599
cells that can generate oligodendrocytes in vivo and can also generate astrocytes and neurons in vitro. Nonetheless, the substantial majority of NG2 glia in the mature CNS appear to be nonmitotic, but like astrocytes, they may retain the function of stem cells in the brain throughout maturation and adulthood. In addition, self-renewing and multipotent neural stem cells are widespread in the ventricle walls of the adult CNS. These neural stem cells have morphological, physiological, and biochemical/immunological characteristics of astrocytes; those located in the hippocampus and olfactory subendyma generate neurons throughout life. The relative contributions of parenchymal NG2 glia and ‘stem’ astrocytes to gliogenesis in the adult remain to be resolved. See also: Astrocyte: Identification Methods; Glial Cells: Microglia During Normal Brain Aging; Glial Cells:
Astrocytes and Oligodendrocytes During Normal Brain Aging; Microglia Properties; Neural Stem Cells and CNS Diseases; Neural Stem Cells: Adult Neurogenesis; Oligodendrocyte Morphology; Oligodendrocyte and Schwann Cell Identification Methods; Radial Glial Cells: Brain Functions.
Further Reading Alvarez-Buylla A, Garcia-Verdugo JM, and Tramontin AD (2001) A unified hypothesis on the lineage of neural stem cells. Nature Reviews Neuroscience 2: 287–293. Butt AM (2005) Synantocytes: The fifth element. Journal of Anatomy 207: 695–706. Doetsch F (2003) The glial identity of neural stem cells. Nature Neuroscience 6: 1127–1134. Goldman JE (2005) Lineages of astrocytes and oligodendrocytes. In: Kettenmann H and Ransom BR (eds.) Neuroglia, 2nd edn., pp. 72–84. New York: Oxford University Press.
Macroglial Lineages A M Butt, University of Portsmouth, Portsmouth, UK
Neuroepithelium
ã 2009 Published by Elsevier Ltd.
Neurons and macroglia derive from the neuroepithelium, which at the earliest stages of development forms the neural plate. As the neural plate thickens, the neural groove forms and the neural plate closes dorsally to form the neural tube, the lumen of which becomes the ventricular system. The cells lining the ventricles of the neural tube form a primary proliferative zone termed the ventricular zone (VZ), and a secondary proliferative zone called the subventricular zone (SVZ) emerges later from the VZ. The VZ ultimately disappears, but the SFV persists into adulthood within the forebrain. As the neural tube expands, the rostral area delineates into the forebrain, midbrain, and hindbrain, and the caudal neural tube forms the spinal cord. During this regionalization, neural crest cells differentiate from the neural tube and migrate to specific regions to form the neurons and glia of the PNS. Thus, CNS and PNS neural cells have clearly distinct lineages from an early stage.
Introduction Macroglia together with neurons make up the two classes of neural cells in the central nervous system (CNS); both macroglia and neurons have a common neuroectodermal embryonic origin. The three major subtypes of macroglia are astrocytes, oligodendrocytes, and the ependymal cells. The fourth major glial cell type in the CNS is the microglia, which are nonneuronal cells that have a mesodermal origin; microglia originate from macrophages that invade the brain during early development. There are also many glia in the peripheral nervous system (PNS), mainly Schwann cells, together with satellite cells of sensory and sympathetic ganglia and glial cells of the enteric nervous system of the gastrointestinal tract. CNS and PNS neural cells have clearly distinct lineages from an early stage of embryonic development. Astroglia and oligodendroglia are the most numerous and functionally important macroglial cell types; ependymal cells are simple cuboidal cells that line the ventricles in the brain and the central canal in the spinal cord. Astrocytes are morphologically and functionally diverse and have a widespread distribution throughout the brain and spinal cord; astrocytes have the archetypal feature of expressing glial fibrillary acidic protein (GFAP). The two major classes of astrocytes are protoplasmic astrocytes and fibrous astrocytes, which are found in the gray and white matter, respectively. In addition, there are specialized astroglial cells throughout the CNS; for example, radial glia are bipolar astroglial cells that predominate in the developing brain, and Mu¨ller glia and Bergmann glia are specialized astroglia restricted to the retina and cerebellum, respectively. Unlike astroglia, oligodendroglia are highly specialized cells and consequently have a more restricted distribution; oligodendrocytes form the myelin sheaths that insulate axons in the CNS and are most numerous in white matter. Until recently, the accepted model was that macroglia and neurons were derived from separate glial and neural progenitors. However, glial and neuronal lineages are much more closely related than was previously thought. Astrocytes and oligodendrocytes develop from multipotent neural stem cells that also generate neurons. Indeed, astroglial stem cells and oligodendrocyte progenitor cells (OPCs) persist in the mature brain and are potential sources of new neurons in the adult.
Radial Glia Are Neural Stem Cells The neuroepithelial cells of the VZ can be considered multipotent neural stem cells in the sense that their progeny gives rise to all of the neurons and macroglia in the CNS. The first cells that emerge from the neuroepithelium are the radial glia. These are distinguished from neuroepithelial cells by the expression of a number of antigens, including the astroglial markers GFAP, vimentin, and the calcium-binding protein S-100b, as well as the glutamate transporter GLAST, nestin, and tenascin-C. The somatas of radial glial cells are located in the VZ and their processes extend to the opposite wall of the neural tube or the pial surface. Radial glia are the main neural stem cells during development and are responsible for most of the subsequent neurogenesis, giving rise first to neurons and later to astrocytes and some oligodendrocytes by a process of ‘transdifferentiation.’ The majority of oligodendrocytes, however, originate at an early stage of development from glial precursors that are generated in specific sites in the brain and spinal cord. Astrocytes are generated later in development, both from radial glia and from glial precursors that also give rise to oligodendrocytes; the proportion of the final population of astrocytes derived from radial glia and glial precursors depends on the region of the CNS. Radial glia not only produce neurons and glia but also form a scaffold along which newborn progenitors migrate from the SVZ. Moreover, the radial glial cells and astrocytes that differentiate from them retain the function of stem cells in the adult brain.
598 Macroglial Lineages
Glial Restricted Precursors Multipotent neural stem cells (neuroepithelium) do not differentiate into astrocytes and oligodendrocytes directly but, rather, through intermediate lineage-restricted stages. The first of these to develop are the glial-restricted precursors, which are distinguished from neuroepithelial cells by expression of A2B5 and nestin and are localized to the ventral neural tube. Several stages in the development of astrocytes and oligodendrocytes have been distinguished, with the main ones being oligodendrocyte and type2 astrocyte precursors (O2A cells), oligodendrocyte precursors, astrocyte precursors, and NG2-expressing glia. The first stage in the differentiation of oligodendrocytes and probably astrocytes is the bipotential O2A glial precursor, which in vitro can generate either type of glial cell; O2A cells are distinguished by expression of platelet-derived growth factor-a receptors (PDGF-aRs) and NG2, in addition to A2B5. It is uncertain to what extent O2A cells are bipotential in vivo, where they may serve predominantly as OPCs which generate only oligodendrocytes. OPCs express the early oligodendrocyte lineage markers PDGF-aR and NG2 and later the homeobox transcription factor Nkx2.2 and the oligodendrocyte lineage gene Olig2 (basic helix–loop–helix factor). Astrocyte precursors have been isolated from numerous regions of the embryonic CNS; they express A2B5 but not GFAP until a relatively late stage of differentiation, and they are therefore difficult to distinguish from glial precursors and O2A cells. Expression of the extracellular matrix transmembrane protein CD44 may serve as an astrocyte precursor marker. Early glial precursors are small cells, with one or more processes, and are highly mobile, migrating from multiple sites to colonize the entire CNS white and gray matter. They do not express early glial antigens such as PDGF-aR and NG2 until they exit the SVZ, and as they migrate, they begin to acquire markers of OPCs and astrocytes. The relative contributions of O2A cells, OPCs, and astrocyte precursors to gliogenesis in vivo are not clear; they display many similarities and may represent different stages in glial precursor differentiation or distinct lineages that arise separately from neural precursors. Indeed, at least in vitro, glial precursors are not truly lineage restricted in that they can generate neurons, astrocytes, and oligodendrocytes under appropriate culture conditions. In addition, after generating oligodendrocytes during development, a significant population of NG2 glia persists throughout the white and gray matter of the adult brain; the functions of adult NG2 glia are unresolved, but they serve in part as a pool of adult OPCs and they may even be multipotent adult neural stem cells. There are
also GFAP-positive astrocyte-like neural stem cells in specific regions of the adult CNS, and these are multipotent and self-renewing.
Regional Variations In the forebrain, glial precursors in the SVZ migrate along radial glia to their final sites in the white matter and cortex to generate oligodendrocytes and some astrocytes, in addition to adult NG2 glia. Astrocytes are derived from migratory glial precursors and from radial glia. In early forebrain development, oligodendrocyte precursors are generated in localized sites ventrally and migrate dorsally. Later, glial precursors that originate from a large dorsolateral SVZ near the lateral ventricle give rise to oligodendrocytes and some astrocytes. Oligodendrocytes and the diverse astrocyte cell types in the cerebellum are derived predominantly from migratory glial precursors from an area dorsal to the fourth ventricle; Bergmann glia arise from embryonic radial glia and share a common lineage with Purkinje neurons. In the embryonic retina, Muller glia arise from a common precursor with neurons, and astrocytes develop at a later stage from glial precursors that migrate into the retina via the optic nerve; oligodendrocytes are absent from the retina of most species. Most astrocytes in the optic nerve are derived from intrinsic radial-like astroglia, whereas oligodendrocyte precursors migrate into the nerve during the perinatal period. In the spinal cord, oligodendrocytes originate from neural stem cells in the ventral neuroepithelium, which first generate neurons and then oligodendrocyte precursors. Later, oligodendrocyte precursors also originate from dorsal areas. Spinal cord astrocytes appear to be derived from separate astrocyte precursors after neurons and oligodendrocytes; as in other areas of the CNS, astrocytes most likely also arise from radial glia.
Gliogenesis in the Adult Central Nervous System Gliogenesis occurs at a slow rate throughout the adult CNS. New glial cells are born locally, predominantly from parenchymal multipotent glial precursor cells and also, in the case of astrocytes, from division of mature cells. The type of cell produced is determined by locality of the precursors; they mostly produce oligodendrocytes in white matter, whereas astrocytes and oligodendrocytes are produced in the same quantities elsewhere. These glial precursors do not express GFAP, but they do express nestin and NG2. It is not clear that all NG2-expressing glia in the adult CNS are glial precursors. NG2 glia are slowly proliferating
Macroglial Lineages 599
cells that can generate oligodendrocytes in vivo and can also generate astrocytes and neurons in vitro. Nonetheless, the substantial majority of NG2 glia in the mature CNS appear to be nonmitotic, but like astrocytes, they may retain the function of stem cells in the brain throughout maturation and adulthood. In addition, self-renewing and multipotent neural stem cells are widespread in the ventricle walls of the adult CNS. These neural stem cells have morphological, physiological, and biochemical/immunological characteristics of astrocytes; those located in the hippocampus and olfactory subendyma generate neurons throughout life. The relative contributions of parenchymal NG2 glia and ‘stem’ astrocytes to gliogenesis in the adult remain to be resolved. See also: Astrocyte: Identification Methods; Glial Cells: Microglia During Normal Brain Aging; Glial Cells:
Astrocytes and Oligodendrocytes During Normal Brain Aging; Microglia Properties; Neural Stem Cells and CNS Diseases; Neural Stem Cells: Adult Neurogenesis; Oligodendrocyte Morphology; Oligodendrocyte and Schwann Cell Identification Methods; Radial Glial Cells: Brain Functions.
Further Reading Alvarez-Buylla A, Garcia-Verdugo JM, and Tramontin AD (2001) A unified hypothesis on the lineage of neural stem cells. Nature Reviews Neuroscience 2: 287–293. Butt AM (2005) Synantocytes: The fifth element. Journal of Anatomy 207: 695–706. Doetsch F (2003) The glial identity of neural stem cells. Nature Neuroscience 6: 1127–1134. Goldman JE (2005) Lineages of astrocytes and oligodendrocytes. In: Kettenmann H and Ransom BR (eds.) Neuroglia, 2nd edn., pp. 72–84. New York: Oxford University Press.