161 Astrocyte and Oligodendrocyte Crosstalk us-Merzbacher-like disease; PML, progressive multifocal leukoencephalopathy; PNND, paraneoplastic neurological disorders; ROS, Reactive oxygen species; SSPE, subacute sclerosing panencephalitis; TBI, traumatic brain injury; TGF, transforming growth factor; TLR, toll-like receptor; VEGF, vascular endothelial growth factor; VLCFA, very long chain fatty acid; VWM, vanishing white matter. interact with oligodendrocytes will provide a deeper insight into the pathophysiology of neurological disorders that may elucidate new pathways to drug strategies for myelin damage in CNS diseases. Astrocyte and oligodendrocyte cross-talk during brain development In neurogenesis, a ‘gliogenic switch’ occurs and dividing neural stem cells develop into glial cells20,21. From these cells, both astrocyte precursor cells and oligodendrocyte progenitor cells (OPCs) arise21,22. Astrogenesis is mediated through cardiotrophin-1 (CT-1), a factor secreted by cortical neurons. CT-1 induces glial fibrillary acidic protein (GFAP) expression by immature astrocytes through activation of the janus kinase signal transducer and activator of transcription proteins (JAK-STAT). The importance of CT-1 is exemplified by the 50-80% decrease in GFAP expression in CT-1 knock-out mice56. Astrogenesis-related genes are silenced during the neurogenic period through epigenetic mechanisms56-58. Oligodendrogenesis, on the other hand, is subject to a morphogen gradient of Sonic hedgehog (Shh) and bone morphogenic protein (BMP) and OPCs arise on the ventral side of the neural tube59,60. Critical in proliferation and timing of oligodendrocyte maturation is secretion of platelet derived growth factor AA (PDGF-AA) by astrocytes61. Once generated, OPCsmigrate due to chemokines and Shh signalling, all while being guided by astrocytes62. In the optic nerve, astrocytes transiently express high levels of the megalin receptor that regulates the availability of Shh in the microenvironment and thus guides OPC migration. Inhibition of the megalin receptor has been shown to result in impaired migration of OPCs to the optic nerve63. Furthermore, astrocytes tightly control release of BMPs and prevent maturation of OPCs into myelinproducing oligodendrocytes64. Clearly, cross-talk between astrocytes and oligodendrocytes during development is essential for migration and maturation of OPCs through the CNS. Various areas in the brain give rise to different types of astrocytes. Fibrous astrocytes are located in the white matter while protoplasmic astrocytes are present in the grey matter. These phenotypes of astrocytes differ in morphology and expression patterns. One example is the expression of excitatory amino acid transporters (EAATs), which is higher in the white matter and results in extracellular glutamate levels being lower in white than in grey matter3,5,65,66. Additionally, the astrocytic syncytium formed by protoplasmic astrocytes is larger than that of fibrous astrocytes66. The differences observed in morphology and protein expression impact the way these cells interact with their environment and with other glia cells such as oligodendrocytes. During development astrocytes provide critical metabolic support of oligodendrocytes by supplying e.g. sterol regulatory element-binding protein (SREBP) cleavage-activating protein, a protein essential in lipid production. Mice in which SREBP cleavage activating protein is conditionally knocked out in astrocytes, develop microcephaly and a decrease in white matter volume67, indicating the importance of astrocyte-derived lipids in myelination. Astrocytes also provide cholesterol for myelin production, and since cholesterol cannot cross the BBB it has to be synthesized de novo in the CNS by astrocytes and oligodendrocytes3,68,69. However,
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