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  • Review Article
  • Published:

Glial specification in the vertebrate neural tube

Nature Reviews Neuroscience volume 5, pages 409–419 (2004)Cite this article

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.

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Figure 1: Patterning of the neural tube generates unique domains for neuronal progenitors.
Figure 2: Restricted origin of oligodendrocyte precursors in the ventral neural tube.
Figure 3: Pattern formation in the neural tube regulates gliogenesis.
Figure 4: Oligodendrocyte and astrocyte precursors are specified in distinct regions of the ventral neural tube.
Figure 5: Complex interactions regulate the neuron–glial switch in the pMN domain.
Figure 6: Sonic hedgehog signalling regulates oligodendrogenesis in vitro through induction of Olig genes.

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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.

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Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute. Divisions of Newborn Medicine and Hematology, Children's Hospital, and the Program in Neuroscience, Harvard Medical School, 44 Binney Street, D640D, Boston, 02115, Massachusetts, USA

    David H. Rowitch

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DATABASE

Entrez Gene

Dlx2

GFAP

Gli3

Hes1

Irx3

Mash1

Ngn1

Ngn2

Nkx2.2

Olig1

Olig2

PDGFRα

Shh

Smad1

Sox9

Sox10

Stat1

Stat3

FURTHER INFORMATION

Workshop on Astrocyte Function in Health and Disease

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.

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Rowitch, D. Glial specification in the vertebrate neural tube. Nat Rev Neurosci 5, 409–419 (2004). https://doi.org/10.1038/nrn1389

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