Key Points
-
Glia comprise 10–20% of cells in the Drosophila nervous system, and more than 90% of cells in the human brain. This implies that glial function is crucial for the increased complexity of neurological function that has emerged during evolution. The principal macroglial subtypes — astrocytes and oligodendrocytes — are derived from the neuroepithelium.
-
Early studies led to the proposal that development of neurons preceded that of glial subtypes in vivo, and that oligodendrocytes in particular developed mostly at postnatal stages. However, it is now clear that the initial specification of spinal cord oligodendrocytes takes place in the embryo.
-
Indications that neurons and glia might be specified by common mechanisms stemmed from the observation that oligodendrocyte precursor cells (OLPs) emerge from a discrete region in the ventral neural tube, rather than from diffuse locations. Marker analysis indicated that OLP development is initiated in the pMN domain of the spinal cord, which also gives rise to motor neurons.
-
A prolonged period of sonic hedgehog (Shh) activity is necessary to ensure normal cell fate acquisition in pMN-oligodendrocyte progenitors, but later stages of OLP maturation are Shh-independent. The Olig1 and Olig2 genes, which probably act downstream of Shh, are required for establishment of the pMN domain.
-
Olig proteins seem to promote oligodendrocyte cell fate while inhibiting astrocyte development. Studies of Olig1 and Olig2 mutants have demonstrated that OLPs and most astrocyte precursors are established in mutually exclusive domains by molecularly independent mechanisms.
-
In the embryonic brain, OLPs develop primarily from ventral regions of the telencephalon. Astrocytes in the brain derive initially from the neuroepithelium through a radial glial intermediate, whereas at later stages they derive from the dorsolateral subventricular zone.
-
The switch from neuronal to glial production in the pMN domain seems to require the Delta–Notch pathway and the transcription factor Sox9, coupled with downregulation of proneural activity.
-
Forced expression of Olig2 and Nkx2.2 is sufficient for ectopic induction of OLPs and production of oligodendrocytes. But in the wild-type embryo, the Olig2–Nkx2.2 interaction seems to be more relevant at later stages for promoting OLP maturation, rather than for the specification of OLPs.
-
Neural specification in vivo is context-dependent and tightly linked to position within the developing CNS, but such anatomical and spatial constraints seem to be less relevant in culture. For example, in neurosphere assays, single neural stem cells from various dorsoventral levels of the CNS can behave as tripotent cells that give rise to neurons, astrocytes and oligodendrocytes.
-
The availability of robust and specific markers for glial lineage development should facilitate assessment of the contributions of glia and their precursors to a range of human neurological disorders, including multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer's disease.
Abstract
Vertebrate macroglial cells have diverse roles in the maintenance of neurological function. This review highlights progress in our understanding of the mechanisms that underlie the specification of precursors for two key macroglial subtypes — oligodendrocytes and astrocytes — in the embryo. These mechanisms are strikingly similar to those that underlie the development of neuronal subtypes, including emergence from localized regions of the neural tube, and involvement of common signalling pathways and downstream transcription factors. The switch from neuronal to glial precursor production can be modelled as a complex interplay between regionally-restricted components and generalized temporal regulators.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Ramón y Cajal, S. Histologie du Systeme Nerveux de l'Homme et des Vertebres (Consejo Superior de Investigaciones Cientificas Instituto 'Ramon y Cajal', Madrid, 1952).
Kettenmann, H. & Ransom, B. R. Neuroglia (Oxford Univ. Press, 1995).
Bennett, M. V., Contreras, J. E., Bukauskas, F. F. & Saez, J. C. New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci. 26, 610–617 (2003).
Ubink, R., Calza, L. & Hokfelt, T. 'Neuro'-peptides in glia: focus on NPY and galanin. Trends Neurosci. 26, 604–609 (2003).
Newman, E. A. New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci. 26, 536–542 (2003).
Barres, B. A. & Barde, Y. Neuronal and glial cell biology. Curr. Opin. Neurobiol. 10, 642–648 (2000).
Lin, S. C. & Bergles, D. E. Synaptic signaling between GABAergic interneurons and oligodendrocyte precursor cells in the hippocampus. Nature Neurosci. 7, 24–32 (2004).
Ling, E. A. & Wong, W. C. The origin and nature of ramified and amoeboid microglia: a historical review and current concepts. Glia 7, 9–18 (1993).
Doetsch, F., Caillé, I., Lim, D. A., García-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).
Malatesta, P. et al. Neuronal or glial progeny: regional differences in radial glia fate. Neuron 37, 751–764 (2003). This study describes neuronal progeny of radial glia in the telencephalon and establishes specific roles for this class of progenitors during neurogenesis.
Goldman, S. Glia as neural progenitor cells. Trends Neurosci. 26, 590–596 (2003).
Rakic, P. Elusive radial glial cells: historical and evolutionary perspective. Glia 43, 19–32 (2003).
Sanai, N. et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427, 740–744 (2004). The investigators identified a multipotent glial progenitor near the lateral ventricle of humans but not other vertebrates. Unlike SVZ progenitors, there was no evidence of contribution to the rostral migratory stream. This population evidently constitutes a new class of endogenous neural progenitor cell in humans.
Parnavelas, J. G. & Nadarajah, B. Radial glial cells: are they really glia? Neuron 31, 881–884 (2001).
Svendsen, C. N. The amazing astrocyte. Nature 417, 29–32 (2002).
Zhang, S. C. Defining glial cells during CNS development. Nature Rev. Neurosci. 2, 840–843 (2001).
Altman, J. A. & Bayer, S. A. Development of the Cerebellar System (CRC, New York, 1997).
Lumsden, A. & Krumlauf, R. Patterning the vertebrate neuraxis. Science 274, 1109–1115 (1996).
Puelles, L. & Rubenstein, J. L. Forebrain gene expression domains and the evolving prosomeric model. Trends Neurosci. 26, 469–476 (2003).
Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20–29 (2000).
McMahon, A. P., Ingham, P. W. & Tabin, C. J. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 53, 1–114 (2003).
Briscoe, J., Pierani, A., Jessell, T. M. & Ericson, J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 101, 435–445 (2000). This important study showed that expression of various homeodomain proteins in the ventral neural tube is differentially regulated by Shh signalling. The combinatorial expression of these proteins in turn determines the identity of neuronal progenitors.
Warf, B. C., Fok-Seang, J. & Miller, R. H. Evidence for the ventral origin of oligodendrocyte precursors in the rat spinal cord. J. Neurosci. 11, 2477–2488 (1991).
Choi, B. H. Radial glia of developing human fetal spinal cord: Golgi, immunohistochemical and electron microscopic study. Brain Res. 227, 249–267 (1981).
Pringle, N. P. & Richardson, W. D. A singularity of PDGF alpha-receptor expression in the dorsoventral axis of the neural tube may define the origin of the oligodendrocyte lineage. Development 117, 525–533 (1993).
Timsit, S. et al. Oligodendrocytes originate in a restricted zone of the embryonic ventral neural tube defined by DM-20 mRNA expression. J. Neurosci. 15, 1012–1024 (1995).
Ono, K., Bansal, R., Payne, J., Rutishauser, U. & Miller, R. H. Early development and dispersal of oligodendrocyte precursors in the embryonic chick spinal cord. Development 121, 1743–1754 (1995).
Richardson, W. D. et al. Oligodendrocyte lineage and the motor neuron connection. Glia 29, 136–142 (2000).
Richardson, W. D. in Glial Cell Development (eds Jessen, K. R. & Richardson, W. D.) 21–54 (Oxford Univ. Press, 2001).
Miller, R. H. Regulation of oligodendrocyte development in the vertebrate CNS. Prog. Neurobiol. 67, 451–467 (2002).
Orentas, D. M., Hayes, J. E., Dyer, K. L. & Miller, R. H. Sonic hedgehog signaling is required during the appearance of spinal cord oligodendrocyte precursors. Development 126, 2419–2429 (1999).
Alberta, J. A. et al. Sonic hedgehog is required during an early phase of oligodendrocyte development in mammalian brain. Mol. Cell. Neurosci. 18, 434–441 (2001).
Soula, C. et al. Distinct sites of origin of oligodendrocytes and somatic motoneurons in the chick spinal cord: oligodendrocytes arise from Nkx2.2-expressing progenitors by a Shh-dependent mechanism. Development 128, 1369–1379 (2001).
Poncet, C. et al. Induction of oligodendrocyte progenitors in the trunk neural tube by ventralizing signals: effects of notochord and floor plate grafts, and of sonic hedgehog. Mech. Dev. 60, 13–32 (1996).
Pringle, N. P. et al. Determination of neuroepithelial cell fate: induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog. Dev. Biol. 177, 30–42 (1996).
Ericson, J., Morton, S., Kawakami, A., Roelink, H. & Jessell, T. M. Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87, 661–673 (1996).
Tsai, H. H. et al. The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110, 373–383 (2002).
Lu, Q. R. et al. Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 25, 317–329 (2000).
Takebayashi, H. et al. Dynamic expression of basic helix-loop-helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3. Mech. Dev. 99, 143–148 (2000).
Zhou, Q., Wang, S. & Anderson, D. J. Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron 25, 331–343 (2000).
Park, H. C., Mehta, A., Richardson, J. S. & Appel, B. olig2 is required for zebrafish primary motor neuron and oligodendrocyte development. Dev. Biol. 248, 356–368 (2002).
Bai, C. B., Stephen, D. & Joyner, A. L. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev. Cell 6, 103–115 (2004).
Novitch, B. G., Chen, A. I. & Jessell, T. M. Coordinate regulation of motor neuron subtype identity and pan-neuronal properties by the bHLH repressor Olig2. Neuron 31, 773–789 (2001).
Liu, R. et al. Region-specific and stage-dependent regulation of Olig gene expression and oligodendrogenesis by Nkx6.1 homeodomain transcription factor. Development 130, 6221–6231 (2003).
Zhou, Q. & Anderson, D. J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109, 61–73 (2002). Analysis of compound Olig1/2 mutant embryos revealed an absence of pMN formation and a ventrally expanded p2 domain. This caused a shift from production of motor neurons and oligodendrocytes to V2 interneurons and astrocytes. So, the pMN and p2 domains represent mutually exclusive regions of oligodendrocyte and astrocyte development, respectively. Olig genes couple neuronal and glial subtype specification, unlike proneural bHLH factors, which control the neuron versus glia decision.
Lu, Q. R. et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109, 75–86 (2002). These authors used mutational analysis to show that Olig1 and Olig2 are functionally distinct. Olig2 is regionally required for motor neuron and oligodendrocyte production in the spinal cord, whereas Olig1 function in oligodendrocyte development is only relevant in the brain. Together with Ref. 45, this paper shows the spectrum of phenotypes that are caused by Olig loss-of-function.
Takebayashi, H. et al. The basic helix-loop-helix factor olig2 is essential for the development of motoneuron and oligodendrocyte lineages. Curr. Biol. 12, 1157–1163 (2002).
Muhr, J., Andersson, E., Persson, M., Jessell, T. M. & Ericson, J. Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube. Cell 104, 861–873 (2001).
Mizuguchi, R. et al. Combinatorial roles of olig2 and neurogenin2 in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons. Neuron 31, 757–771 (2001).
Zhou, Q., Choi, G. & Anderson, D. J. The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2. Neuron 31, 791–807 (2001). This study shows how combinatorial interactions of Olig2 and Nkx2.2 promote oligodendrocyte development, and demonstrates the role of Ngn in inhibiting gliogenesis. The data support a model whereby Ngn downregulation is necessary for the neuronal–glial switch.
Edlund, T. & Jessell, T. M. Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system. Cell 96, 211–224 (1999).
Temple, S. The development of neural stem cells. Nature 414, 112–117 (2001).
Anderson, D. J. Stem cells and pattern formation in the nervous system: the possible versus the actual. Neuron 30, 19–35 (2001).
Lillien, L. E. & Raff, M. C. Differentiation signals in the CNS: type-2 astrocyte development in vitro as a model system. Neuron 5, 111–119 (1990).
Raff, M. C., Miller, R. H. & Noble, M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 303, 390–396 (1983).
Fulton, B. P., Burne, J. F. & Raff, M. C. Glial cells in the rat optic nerve. The search for the type-2 astrocyte. Ann. NY Acad. Sci. 633, 27–34 (1991).
Kondo, T. & Raff, M. C. A role for Noggin in the development of oligodendrocyte precursor cells. Dev. Biol. 267, 242–251 (2004).
Rao, M. S., Noble, M. & Mayer-Proschel, M. A tripotential glial precursor cell is present in the developing spinal cord. Proc. Natl Acad. Sci. USA 95, 3996–4001 (1998).
Gregori, N., Proschel, C., Noble, M. & Mayer-Proschel, M. The tripotential glial-restricted precursor (GRP) cell and glial development in the spinal cord: generation of bipotential oligodendrocyte–type-2 astrocyte progenitor cells and dorsal–ventral differences in GRP cell function. J. Neurosci. 22, 248–256 (2002).
Lee, J. C., Mayer-Proschel, M. & Rao, M. S. Gliogenesis in the central nervous system. Glia 30, 105–121 (2000).
Pringle, N. P., Guthrie, S., Lumsden, A. & Richardson, W. D. Dorsal spinal cord neuroepithelium generates astrocytes but not oligodendrocytes. Neuron 20, 883–893 (1998).
Pringle, N. P. et al. Fgfr3 expression by astrocytes and their precursors: evidence that astrocytes and oligodendrocytes originate in distinct neuroepithelial domains. Development 130, 93–102 (2003).
Spassky, N. et al. Multiple restricted origin of oligodendrocytes. J. Neurosci. 18, 8331–8343 (1998).
Tekki-Kessaris, N. et al. Hedgehog-dependent oligodendrocyte lineage specification in the telencephalon. Development 128, 2545–2554 (2001).
Spassky, N. et al. Sonic hedgehog-dependent emergence of oligodendrocytes in telencephalon: evidence for a source of oligodendrocytes in the olfactory bulb that is independent of PDGFRα signaling. Development 128, 4993–5004 (2001).
Nery, S., Wichterle, H. & Fishell, G. Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. Development 128, 527–540 (2001).
He, W., Ingraham, C., Rising, L., Goderie, S. & Temple, S. Multipotent stem cells from the mouse basal forebrain contribute GABAergic neurons and oligodendrocytes to the cerebral cortex during embryogenesis. J. Neurosci. 21, 8854–8862 (2001).
Marshall, C. A. & Goldman, J. E. Subpallial dlx2-expressing cells give rise to astrocytes and oligodendrocytes in the cerebral cortex and white matter. J. Neurosci. 22, 9821–9830 (2002).
Ivanova, A. et al. Evidence for a second wave of oligodendrogenesis in the postnatal cerebral cortex of the mouse. Neurosci. Res. 73, 581–592 (2003).
Luskin, M. B., Pearlman, A. L. & Sanes, J. R. Cell lineage in the cerebral cortex of the mouse studied in vivo and in vitro with a recombinant retrovirus. Neuron 1, 635–647 (1988).
Price, J. & Thurlow, L. Cell lineage in the rat cerebral cortex: a study using retroviral-mediated gene transfer. Development 104, 473–482 (1988).
Levison, S. W. and Goldman, J. E. Both oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain. Neuron 10, 201–212 (1993).
Parnavelas, J. G. Glial cell lineages in the rat cerebral cortex. Exp. Neurol. 156, 418–429 (1999).
Schuurmans, C. & Guillemot, F. Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr. Opin. Neurobiol. 12, 26–34 (2002).
Bertrand, N., Castro, D. S. & Guillemot, F. Proneural genes and the specification of neural cell types. Nature Rev. Neurosci. 3, 517–530 (2002).
Nieto, M., Schuurmans, C., Britz, O. & Guillemot, F. Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron 29, 401–413 (2001).
Ross, S. E., Greenberg, M. E. & Stiles, C. D. Basic helix-loop-helix factors in cortical development. Neuron 39, 13–25 (2003).
Sun, Y. et al. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104, 365–376 (2001). This interesting study shows that Ngn1 uses distinct transcriptional mechanisms to induce neurogenesis and inhibit the differentiation of neural stem cells into astrocytes. It provides a rationale for how such bHLH proteins might regulate the neuronal–glial switch.
Gross, R. E. et al. Bone morphogenetic proteins promote astroglial lineage commitment by mammalian subventricular zone progenitor cells. Neuron 17, 595–606 (1996).
Bonni, A. et al. Regulation of gliogenesis in the central nervous system by the JAK–STAT signaling pathway. Science 278, 477–483 (1997).
Mabie, P. C., Mehler, M. F. & Kessler, J. A. Multiple roles of bone morphogenetic protein signaling in the regulation of cortical cell number and phenotype. J. Neurosci. 19, 7077–7088 (1999).
Nakashima, K. et al. Synergistic signaling in fetal brain by STAT3–Smad1 complex bridged by p300. Science 284, 479–482 (1999).
Gabay, L., Lowell, S., Rubin, L. L. & Anderson, D. J. Deregulation of dorsoventral patterning by FGF confers trilineage differentiation capacity on CNS stem cells in vitro. Neuron 40, 485–499 (2003). These authors investigated the phenomenon of multipotent neural stem cell capabilities in culture, and they found that both Olig2+ and Olig− cells could form multipotent neurospheres. The clonogenic competence to generate neurons, astrocytes and oligodendrocytes entailed a deregulation of dorsoventral identity under in vitro culture conditions, raising the question of whether such tripotent cells actually exist in vivo.
Fukuda, S., Kondo, T., Takebayashi, H. & Taga, T. Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway. Cell Death Differ. 11, 196–202 (2004).
Wu, Y., Liu, Y., Levin, E. M. & Rao, M. S. Hes1 but not Hes5 regulates an astrocyte versus oligodendrocyte fate choice in glial restricted precursors. Dev. Dyn. 226, 675–689 (2003).
Sussman, C. R., Davies, J. E. & Miller, R. H. Extracellular and intracellular regulation of oligodendrocyte development: roles of Sonic hedgehog and expression of E proteins. Glia 40, 55–64 (2002).
Park, H. C. & Appel, B. Delta-Notch signaling regulates oligodendrocyte specification. Development 130, 3747–3755 (2003). These investigators found that mutations in the zebrafish Notch pathway resulted in failure to produce oligodendrocytes. They argue that Notch signalling preserves subsets of ventral spinal cord precursors during neurogenesis, acting with other temporally and spatially restricted factors to specify them for oligodendrocyte fate.
Gaiano, N., Nye, J. S. & Fishell, G. Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron 26, 395–404 (2000).
Chambers, C. B. et al. Spatiotemporal selectivity of response to Notch1 signals in mammalian forebrain precursors. Development 128, 689–702 (2001).
Scheer, N., Groth, A., Hans, S. & Campos-Ortega, J. A. An instructive function for Notch in promoting gliogenesis in the zebrafish retina. Development 128, 1099–1107 (2001).
Wang, S. et al. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 21, 63–75 (1998).
Itoh, M. et al. Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev. Cell 4, 67–82 (2003).
Sauvageot, C. M. & Stiles, C. D. Molecular mechanisms controlling cortical gliogenesis. Curr. Opin. Neurobiol. 12, 244–249 (2002).
Hosoya, T., Takizawa, K., Nitta, K. & Hotta, Y. glial cells missing: a binary switch between neuronal and glial determination in Drosophila. Cell 82, 1025–1036 (1995).
Jones, B. W., Fetter, R. D., Tear, G. & Goodman, C. S. glial cells missing: a genetic switch that controls glial versus neuronal fate. Cell 82, 1013–1023 (1995).
Stolt, C. C. et al. The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev. 17, 1677–1689 (2003). Conditional knockout of Sox9 resulted in failure to specify OLPs on schedule and proportionate increases in the numbers of motor neurons. This indicates that Sox9 is needed to promote a proglial specification programme in the pMN domain.
Qian, X. et al. Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28, 69–80 (2000).
Sun, T. et al. Olig bHLH proteins interact with homeodomain proteins to regulate cell fate acquisition in progenitors of the ventral neural tube. Curr. Biol. 11, 1413–1420 (2001).
Briscoe, J. et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature 398, 622–627 (1999).
Qi, Y. et al. Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor. Development 128, 2723–2733 (2001). This study describes the requirements for Nkx2.2 function in oligodendrocyte maturation but not the specification of OLPs. The data argue strongly against a p3 origin for OLPs in the neural tube of mice. This is consistent with expression data, which show Nkx2.2 proteins in migrating OLPs.
Fu, H. et al. Dual origin of spinal oligodendrocyte progenitors and evidence for the cooperative role of Olig2 and Nkx2.2 in the control of oligodendrocyte differentiation. Development 129, 681–693 (2002).
Stolt, C. C. et al. Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10. Genes Dev. 16, 165–170 (2002).
Chandran, S. et al. FGF-dependent generation of oligodendrocytes by a hedgehog-independent pathway. Development 130, 6599–6609 (2003).
Kessaris, N., Jamen, F., Rubin, L. L. & Richardson, W. D. Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors. Development 131, 1289–1298 (2004).
Raine, C. S. Stage-specific mechanisms contribute to the multiple sclerosis plaque. NeuroScience News 4, 11–21 (2001).
Clement, A. M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113–117 (2003).
Nicoll, J. A. & Weller, R. O. A new role for astrocytes: β-amyloid homeostasis and degradation. Trends Mol. Med. 9, 281–282 (2003).
Jarjour, A. A. et al. Netrin-1 is a chemorepellant for oligodendrocyte precursor cells in the embryonic spinal cord. J. Neurosci. 23, 3735–3744 (2003).
Spassky, N. et al. Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1. J. Neurosci. 22, 5992–6004 (2002).
Xu, X. et al. Selective expression of Nkx-2.2 transcription factor in chicken oligodendrocyte progenitors and implications for the embryonic origin of oligodendrocytes. Mol. Cell. Neurosci. 16, 740–753 (2000).
Mi, H. & Barres, B. A. Purification and characterization of astrocyte precursor cells in the developing rat optic nerve. J. Neurosci 19, 1049–1061 (1999).
Qi, Y., Tan, M., Hui, C. C. & Qiu, M. Gli2 is required for normal Shh signaling and oligodendrocyte development in the spinal cord. Mol. Cell. Neurosci. 23, 440–450 (2003).
Lee, J. et al. Neurogenin3 participates in gliogenesis in the developing vertebrate spinal cord. Dev. Biol. 253, 84–98 (2003).
Armstrong, R. C., Kim, J. G. & Hudson, L. D. Expression of myelin transcription factor I (MyTI), a 'zinc-finger' DNA-binding protein, in developing oligodendrocytes. Glia 14, 303–321 (1995).
Mekki-Dauriac, S. et al. Bone morphogenetic proteins negatively control oligodendrocyte precursor specification in the chick spinal cord. Development 129, 5117–5130 (2002).
Acknowledgements
I am grateful to R. Bachoo, A. Alvarez-Buylla, M. Freeman, F. Guillemot, K. Ligon, M. Qui, B. Richardson and C. Stiles for comments and stimulating discussions, to F. Guillemot for communication of unpublished results, and to U. DeGirolomi for assistance in translating the Cajal quotation. I would also like to acknowledge the helpful comments of anonymous reviewers, and apologize to those whose work I failed to cite because of the limited scope of the review. Work in my laboratory is supported by the National Institutes of Health, the James S. McDonnell Foundation and the National Multiple Sclerosis Society.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Glossary
- SALTATORY NERVE CONDUCTION
-
A process of rapid impulse conduction that is conferred on axons by myelin sheaths in which an action potential 'leaps' from one node of Ranvier (the exposed region of the axons between adjacent myelin sheaths) to the next.
- SUBVENTRICULAR ZONE
-
(SVZ). A layer of cells in the developing brain that is generated by the migration of neuroblasts from the adjoining ventricular zone.
- PULSE–CHASE LABELLING STUDIES
-
Experiments in which addition of a radioactive amino acid (pulse) is followed by non-labelled amino acid (chase), and the production of radioactive proteins from the amino-acid precursors is monitored.
- RHOMBIC LIP
-
A germinal epithelium that is located between the fourth ventricle and the roof plate in the metencephalon.
- BONE MORPHOGENETIC PROTEINS
-
(BMPs). Multifunctional secreted proteins of the transforming growth factor-β superfamily. In the early embryo, they participate in dorsoventral patterning.
- ROOF PLATE
-
The point of fusion of the neural folds, which forms the dorsal-most part of the neural tube.
- BASIC HELIX-LOOP-HELIX
-
(bHLH). A structural motif present in many transcription factors that is characterized by two α-helices separated by a loop. The helices mediate dimerization, and the adjacent basic region is required for DNA binding.
- GREEN FLUORESCENT PROTEIN
-
(GFP). Fluorescent protein cloned from the jellyfish Aequoria victoria. The most frequently used mutant, enhanced GFP, is excited at 488 nm and has an emission maximum at 510 nm.
- FLUORESCENCE-ACTIVATED CELL SORTING
-
(FACS). A method in which dissociated and individual living cells are sorted, in a liquid stream, according to the intensity of fluorescence that they emit as they pass through a laser beam.
- GANGLIONIC EMINENCE
-
The proliferative zone of the ventral telencephalon, which gives rise to the basal ganglia, and also generates some cortical neurons and glia. It consists of lateral, caudal and medial subdivisions.
- E-PROTEINS
-
Transcription factors of the basic helix-loop-helix class, which are closely related to the Daughterless protein of Drosophila.
- CRE/LOXP
-
A site-specific recombination system derived from Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre-recombinase enzyme catalyses recombination between the loxP sites, leading to excision of the intervening sequence.
- NEUROSPHERES
-
Aggregates of neural precursor cells.
- MULTIPLE SCLEROSIS
-
A neurodegenerative disorder characterized by demyelination of CNS tracts. Symptoms depend on the site of demyelination and include sensory loss, weakness in leg muscles, speech difficulties, loss of coordination and dizziness.
- AMYOTROPHIC LATERAL SCLEROSIS
-
A progressive neurological disease that is associated with the degeneration of central and spinal motor neurons. This neuron loss causes muscles to weaken and waste away, leading to paralysis.
Rights and permissions
About this article
Cite this article
Rowitch, D. Glial specification in the vertebrate neural tube. Nat Rev Neurosci 5, 409–419 (2004). https://doi.org/10.1038/nrn1389
Issue Date:
DOI: https://doi.org/10.1038/nrn1389
This article is cited by
-
Potential of Nano-Engineered Stem Cells in the Treatment of Multiple Sclerosis: A Comprehensive Review
Cellular and Molecular Neurobiology (2024)
-
Ferroptosis in oligodendrocyte progenitor cells mediates white matter injury after hemorrhagic stroke
Cell Death & Disease (2022)
-
Oligodendroglia heterogeneity in the human central nervous system
Acta Neuropathologica (2022)
-
Region-specific distribution of Olig2-expressing astrocytes in adult mouse brain and spinal cord
Molecular Brain (2021)
-
Survival control of oligodendrocyte progenitor cells requires the transcription factor 4 during olfactory bulb development
Cell Death & Disease (2021)