ReviewMolecular mechanisms controlling cortical gliogenesis
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:
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