Received: 15 August, 2007. Accepted: 28 September, 2007. Invited Review Functional Development and Embryology ©2007 Global Science Books Oligodendrocyte Myelination in the Mammalian CNS Q. Richard Lu * • Veerakumar Balasubramaniyan • Raniero L. Peru Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Corresponding author: * qrichard.lu@utsouthwestern.edu ABSTRACT Oligodendrocyte myelination is essential for the proper function of the mammalian central nervous system. The generation of myelinating oligodendrocytes is regulated by complex but coordinated signals during CNS development. Recent discoveries of critical transcriptional regulators for oligodendrocyte differentiation and axonal signals for myelin sheath production have significantly advanced our understanding of the molecular mechanisms governing oligodendrocyte myelinogenesis. This review highlights current perspectives on the origin of oligodendrocytes and the intrinsic and extrinsic regulation of oligodendrocyte differentiation and myelinogenesis. Potential implications of myelin in health and disease are also explored. _____________________________________________________________________________________________________________ Keywords: epigenetic, glial, neuregulin, Olig1, Olig2, origin, Sox, transcriptional regulation Abbreviations: AEP, anterior entopeduncular area; BDNF, brain-derived neurotrophic factor; BMP, bone morphogenetic protein; CNS, central nervous system; FGF, fibroblast growth factor; GRP, glial restricted precursors; LGE, lateral ganglion eminence; LIF, leukemia inhibitory factor, MBP, myelin basic protein; MGE, medial ganglion eminence; NGF, nerve growth factor; NRG, neuregulin; NT3, neurotrophin-3; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor alpha; PLP, proteolipid protein; PSA-NCAM, polysialic acid-neural cell adhesion molecule; Shh, sonic hedgehog; SVZ, subventricular zone; TSA, Trichostatin A CONTENTS INTRODUCTION...................................................................................................................................................................................... 118 ORIGINS OF OLIGODENDROCYTES DURING CNS DEVELOPMENT ............................................................................................ 119 Oligodendrocyte specification in the developing spinal cord ................................................................................................................ 119 Oligodendrocyte specification in the developing brain.......................................................................................................................... 119 Oligodendrocytes in the adult brain ....................................................................................................................................................... 120 Oligodendrocyte lineage development .................................................................................................................................................. 120 INTRINSIC CONTROL OF OLIGODENDROCYTE MATURATION.................................................................................................... 120 bHLH factor family ............................................................................................................................................................................... 121 HMG domain containing Sox gene family ............................................................................................................................................ 122 Homeodomain protein family ................................................................................................................................................................ 122 Zinc finger protein family...................................................................................................................................................................... 122 Epigenetic control of oligodendrocyte differentiation ........................................................................................................................... 123 EXTRINSIC CONTROL OF OLIGODENDROCYTE MATURATION................................................................................................... 123 Axonal signals in myelination ............................................................................................................................................................... 123 Neuregulin ........................................................................................................................................................................................ 123 Neurotrophic factors ......................................................................................................................................................................... 124 Electrical activity .............................................................................................................................................................................. 124 Extra cellular matrix proteins ............................................................................................................................................................ 125 MYELINATION IN HEALTH AND DISEASE ........................................................................................................................................ 125 CONCLUDING REMARKS ..................................................................................................................................................................... 126 ACKNOWLEDGEMENTS ....................................................................................................................................................................... 126 REFERENCES........................................................................................................................................................................................... 126 _____________________________________________________________________________________________________________ INTRODUCTION Myelination is the evolutionary conserved process by which myelin sheath spirally wraps around axons to insu- late them (Raine 1984). Axonal insulation by oligodendro- cytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS) enhances sal- tatory conduction, which is essential for the normal func- tion of the vertebrate nervous system, particularly for motor and cognitive functions. Myelination between exposed nodes of Ranvier allows action potentials to propagate ef- ficiently and maximizes axonal conduction velocity in a spatially-compact manner. Although a few invertebrates possess a myelin-like structure, axonal ensheathment by compact myelin is a unique feature of the vertebrate nervous system (Zalc and Colman 2000). Various pathological in- sults and nerve injuries may damage CNS myelin and there- fore disrupt normal transmission of nerve impulses, eventu- ally leading to myelin-related disorders such as multiple sclerosis and the leukodystrophies (Berger et al. 2001; Trapp et al. 1998). At present, the mechanisms underlying myelinating disease formation and myelin repair are poorly understood. Oligodendrocytes in rodents are generated during em-