Review
Molecular mechanisms controlling cortical gliogenesis

https://doi.org/10.1016/S0959-4388(02)00322-7Get rights and content

Abstract

The sequential appearance of neurons and glia in the vertebrate central nervous system may be governed by competition between growth factor signaling pathways and downstream transcription factors. In cortical progenitor cell cultures, the proneural basic helix–loop–helix transcription factor Ngn1 suppresses formation of astrocytes by sequestering coactivator proteins that are required by signal transducers and activators of transcription for the expression of astrocyte-specific genes. In the developing neural tube, combinatorial interactions between the proneural transcription factor Ngn2 and the basic helix–loop–helix transcription factor Olig2 specify the formation of motor neurons or oligodendrocytes.

Introduction

Genetically accessible organisms such as Drosophila melanogaster and Caenorhabditis elegans have provided useful insights into the mechanisms whereby transcription factors direct the formation of vertebrate neurons from multipotent progenitor cells [1]. However, vertebrate glia are anatomically and functionally distinct from their counterparts in flies and worms. Moreover, neurons and glia in the vertebrate central nervous system arise sequentially from common progenitor cells, a chain of events that is not recapitulated in invertebrate model systems.

What are the genes that direct the formation of vertebrate glia? How do vertebrate neurons and glia arise sequentially from common progenitor cells? This review discusses the molecular mechanisms that modulate vertebrate gliogenesis, particularly within the cortex. Fate choice in stem cells is influenced by exposure to extracellular cues, which initiate signal transduction pathways that culminate in the nucleus to affect fate-specific gene transcription. We begin with an overview of the timing of cortical development, and we then progress to a discussion on growth factors and signal transduction pathways that modulate the fate of cortical progenitor cells in culture. We conclude with recent insights into the role of transcription factors in the formation of astrocytes and oligodendrocytes.

Section snippets

The timing of cortical development

Regulation of cell fate acquisition in the vertebrate central nervous system is complex and reliant on both cell-intrinsic factors and position-dependent extracellular cues 2., 3.. An important intrinsic factor is the element of time. The generation of all cell types in the cortex occurs in temporally distinct, albeit overlapping, phases — neurons are generated first, followed by astrocytes, and then oligodendrocytes [4] (Fig. 1a). Two germinal zones arise sequentially during mammalian

Effects of growth factors on cortical stem cells

In vitro, the fate choice decisions of cortical stem cells can be modulated by extracellular cues such as growth factors — including platelet-derived growth factor (PDGF), ciliary neurotrophic factor (CNTF), interleukin 6 (IL6), leukemia inhibitory factor (LIF) and bone morphogenic proteins (BMPs) — and organizing signals such as Sonic hedgehog (Shh; Fig. 1c). Cortical neuroepithelial cells isolated during neurogenesis differentiate into neurons following treatment with PDGF [11]. Members of

Transcription factors and cortical astrocyte development

Transcription factors with basic helix–loop–helix (bHLH) domains promote neuronal determination 1., 24.. Comparable bHLH factors that promote the formation of astrocytes have not been isolated. However, recent studies revealed that changes in the expression of proneural bHLH transcription factors might be a critical event in the switch from neurogenesis to gliogenesis (Fig. 2). Cortical progenitor cells isolated from double knockout mice lacking the proneuronal bHLH genes Ngn2 and Mash1 show

Transcription factors and oligodendrocyte development

Two positive-acting bHLH factors expressed in developing spinal cord and cortex, called Olig1 and Olig2, are involved in oligodendrocyte development 36••., 37••. (Fig. 2). In gain-of-function studies, both Olig genes are sufficient for formation of oligodendrocytes or early oligodendrocyte progenitors 36••., 37••., 38., 39.. In loss-of-function analyses, Olig2 function is required for oligodendrocyte and motor neuron specification in the spinal cord, and determines neural patterning in

Conclusions

Genetically accessible organisms such as Drosophila and C. elegans have been generally uninformative in the domain of vertebrate glial development. Recent insights into the genetic requirements for vertebrate glial development have been derived from analyses of multipotent cortical progenitor cells. In culture, cortical progenitor cells can be induced to form astrocytes or oligodendrocytes by exposure to cytokines or organizing signals such as Shh. Molecular analysis of these factor-induced

Acknowledgements

We thank Gregory Cavanagh for his help in the generation of the curves used Fig. 1a. Work from the author's lab cited here was supported by grants from the National Institutes of Health (HD24296 and N54051) and the Dana Farber-Mahoney Center for Neurooncology.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (45)

  • M.F Mehler et al.

    Bone morphogenetic proteins in the nervous system

    Trends Neurosci

    (1997)
  • K Miyazono

    TGF-beta signaling by Smad proteins

    Cytokine Growth Factor Rev

    (2000)
  • T Furukawa et al.

    Rax, Hes1, and Notch1 promote the formation of Muller glia by postnatal retinal progenitor cells

    Neuron

    (2000)
  • K Tanigaki et al.

    Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate

    Neuron

    (2001)
  • Q.R Lu et al.

    Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system

    Neuron

    (2000)
  • Q Zhou et al.

    Identification of a novel family of oligodendrocyte lineage-specific basic helix–loop–helix transcription factors

    Neuron

    (2000)
  • Q Zhou et al.

    The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2

    Neuron

    (2001)
  • Q.R Lu et al.

    Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection

    Cell

    (2002)
  • Q Zhou et al.

    The bHLH transcription factors Olig2 and Olig1 couple neuronal and glial subtype specification

    Cell

    (2002)
  • R Mizuguchi et al.

    Combinatorial roles of Olig2 and Neurogenin2 in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons

    Neuron

    (2001)
  • B.G Novitch et al.

    Coordinate regulation of motor neuron subtype identity and pan-neuronal properties by the bHLH repressor Olig2

    Neuron

    (2001)
  • S Wang et al.

    A role for the helix–loop–helix protein Id2 in the control of oligodendrocyte development

    Neuron

    (2001)
  • Cited by (288)

    • Development of the Blood-Brain Barrier in Ducks

      2022, Microscopy and Microanalysis
    View all citing articles on Scopus
    View full text