Specification of CNS glia from neural stem cells in the embryonic neuroepithelium

Abstract

All the neurons and glial cells of the central nervous system are generated from the neuroepithelial cells in the walls of the embryonic neural tube, the 'embryonic neural stem cells'. The stem cells seem to be equivalent to the so-called 'radial glial cells', which for many years had been regarded as a specialized type of glial cell. These radial cells generate different classes of neurons in a position-dependent manner. They then switch to producing glial cells (oligodendrocytes and astrocytes). It is not known what drives the neuron-glial switch, although downregulation of pro-neural basic helix-loop-helix transcription factors is one important step. This drives the stem cells from a neurogenic towards a gliogenic mode. The stem cells then choose between developing as oligodendrocytes or astrocytes, of which there might be intrinsically different subclasses. This review focuses on the different extracellular signals and intracellular responses that influence glial generation and the choice between oligodendrocyte and astrocyte fates.

Figure 1

Developmental sites of origin of OLPs. The diagrams depict the sites of origin and migration pathways of OLPs during embryonic and perinatal development. (a) Drawings of coronal sections through the developing telencephalon at the indicated ages. Colour marks the sites of origin of OLPs in the VZ and arrows show their presumed migration pathways. (b) Transverse sections of the cervical spinal cord showing the early ventral and later dorsal sources along with their dispersal routes. Note: The brain sections are drawn to scale relative to each other, as are the spinal cord sections, but the spinal cord is drawn disproportionately large compared with the brain. The ventral sources of OLPs are induced by Shh from the floor plate of the spinal cord or the VZ of the ventral forebrain. The dorsal sources (including the cerebral cortex of the brain) are thought to be Shh independent, possibly relying on fibroblast growth factor. Dorsal OLP generation might also be helped by BMP downregulation in dorsal structures during later embryonic development. See text for a more complete description. E13, embryonic day 13; E15, embryonic day 15; PO, postnatal day 0.

Figure 2

Signalling pathways involved in the induction of astrocyte specification/differentiation. Astrocyte differentiation is thought to be induced via cytokine and/or BMP signalling pathways. Cytokines (LIF or CNTF) induce dimerization of the LIF receptor (LIFR) with co-receptor gp130, leading to phosphorylation and activation of Janus kinases (Jaks). Receptor dimerization also creates docking sites for the transcription factor Stat3, which is tyrosine phosphorylated by Jaks. The phosphorylated Stats dimerize and move into the nucleus, recruiting p300 and binding to specific sequences in the GFAP promoter. BMP dimers induce the tetramerization of the BMPR-I and BMPR-II receptors, which are serine–threonine kinases. BMPR-II then phosphorylates and activates BMPR-I, which phosphorylates Smad1. Phosphorylated Smad1 associates with Smad4 (unknown stoichiometry) and the complex moves into the nucleus, recruiting p300 and CBP, which probably bind directly to the GFAP promoter and initiate transcription. Smads and Stats bind opposite ends of p300, which presumably allows synergistic integration of LIF/CNTF and BMP signalling pathways. These signalling pathways can be inhibited by neurogenins, which are thought to act by blocking Stat dimerization and also by sequestering p300. The activity of neurogenin can be inhibited, in an undefined manner, by growth hormone. Notch signalling (via the cleaved/released intracellular domain) might also interact with the Stat pathway. See text for a fuller description.