Origin of Oligodendrocytes in the Subventricular Zone of the Adult Brain

Glial fibrillary acidic protein (GFAP)-positive astrocytes (type B cells) in the subventricular zone (SVZ) generate large numbers of new neurons in the adult brain. SVZ stem cells can also generate oligodendrocytes in vitro, but it is not known whether these adult primary progenitors generate oligodendrocytes in vivo. Myelin repair and oligodendrocyte formation in the adult brain is instead associated with glial-restricted progenitors cells, known as oligodendrocyte progenitor cells (OPCs). Here we show that type B cells also generate a small number of nonmyelinating NG2-positive OPCs and mature myelinating oligodendrocytes. Some type B cells and a small subpopulation of actively dividing type C (transit-amplifying) cells expressed oligodendrocyte lineage transcription factor 2 (Olig2), suggesting that oligodendrocyte differentiation in the SVZ begins early in the lineage. Olig2-positive, polysialylated neural cell adhesion molecule-positive, PDGF receptor α-positive, and β-tubulin-negative cells originating in the SVZ migrated into corpus callosum, striatum, and fimbria fornix to differentiate into the NG2-positive nonmyelinating and mature myelinating oligodendrocytes. Furthermore, primary clonal cultures of type B cells gave rise to oligodendrocytes alone or oligodendrocytes and neurons. Importantly, the number of oligodendrocytes derived from type B cells in vivo increased fourfold after a demyelinating lesion in corpus callosum, indicating that SVZ astrocytes participate in myelin repair in the adult brain. Our work identifies SVZ type B cells as progenitors of oligodendrocytes in normal and injured adult brain.

[1]  A. Fasolo,et al.  Glial Tubes in the Rostral Migratory Stream of the Adult Rat , 1997, Brain Research Bulletin.

[2]  D. Rowitch,et al.  Oligodendrocyte development in the spinal cord and telencephalon: common themes and new perspectives , 2001, International Journal of Developmental Neuroscience.

[3]  Brent A. Reynolds,et al.  Multipotent CNS Stem Cells Are Present in the Adult Mammalian Spinal Cord and Ventricular Neuroaxis , 1996, The Journal of Neuroscience.

[4]  E. Parati,et al.  Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[5]  S. Brenner,et al.  The structure of the nervous system of the nematode Caenorhabditis elegans. , 1986, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[6]  Brent A Reynolds,et al.  Neural stem cells and neurospheres—re-evaluating the relationship , 2005, Nature Methods.

[7]  A. Butt.  Structure and function of oligodendrocytes , 2004 .

[8]  Anna Vallstedt,et al.  Multiple Dorsoventral Origins of Oligodendrocyte Generation in the Spinal Cord and Hindbrain , 2005, Neuron.

[9]  P. Sawanpanyalert,et al.  Human Coronavirus Infections in Rural Thailand: A Comprehensive Study Using Real-Time Reverse-Transcription Polymerase Chain Reaction Assays , 2007, The Journal of infectious diseases.

[10]  C. LeBlond,et al.  Radioautographic evidence for slow astrocyte turnover and modest oligodendrocyte production in the corpus callosum of adult mice infused with 3H‐thymidine , 1988, The Journal of comparative neurology.

[11]  W. Blakemore,et al.  Efficient recolonisation of progenitor‐depleted areas of the CNS by adult oligodendrocyte progenitor cells , 2002, Glia.

[12]  A. Álvarez-Buylla,et al.  Network of tangential pathways for neuronal migration in adult mammalian brain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. García-Verdugo,et al.  Radial glia give rise to adult neural stem cells in the subventricular zone. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Brent A. Reynolds,et al.  Neural stem cells in the adult mammalian forebrain: A relatively quiescent subpopulation of subependymal cells , 1994, Neuron.

[15]  S. Goderie,et al.  Multipotent Stem Cells from the Mouse Basal Forebrain Contribute GABAergic Neurons and Oligodendrocytes to the Cerebral Cortex during Embryogenesis , 2001, The Journal of Neuroscience.

[16]  David J Anderson,et al.  Identification of a Novel Family of Oligodendrocyte Lineage-Specific Basic Helix–Loop–Helix Transcription Factors , 2000, Neuron.

[17]  S. Itohara,et al.  Glial protein S100B modulates long-term neuronal synaptic plasticity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Arturo Alvarez-Buylla,et al.  Chain Migration of Neuronal Precursors , 1996, Science.

[19]  Anne Baron-Van Evercooren,et al.  Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Y. Qi,et al.  Origin and molecular specification of oligodendrocytes in the telencephalon , 2002, Trends in Neurosciences.

[21]  S. Levison,et al.  Both oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain , 1993, Neuron.

[22]  C. Lois,et al.  Long-distance neuronal migration in the adult mammalian brain. , 1994, Science.

[23]  J. García-Verdugo,et al.  Composition and organization of the SCZ: a large germinal layer containing neural stem cells in the adult mammalian brain. , 2006, Cerebral cortex.

[24]  L. Decker,et al.  Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination , 1999, The European journal of neuroscience.

[25]  D. Rowitch.  Glial specification in the vertebrate neural tube , 2004, Nature Reviews Neuroscience.

[26]  D. Chari,et al.  Remyelination In Multiple Sclerosis , 2007, International Review of Neurobiology.

[27]  Maria B. Luskin,et al.  Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone , 1993, Neuron.

[28]  R. Reynolds,et al.  NG2‐expressing cells as oligodendrocyte progenitors in the normal and demyelinated adult central nervous system , 2005, Journal of anatomy.

[29]  T. Weissman,et al.  Neurons derived from radial glial cells establish radial units in neocortex , 2001, Nature.

[30]  J. Hinds,et al.  Gliogenesis of astrocytes and oligodendrocytes in the neocortical grey and white matter of the adult rat: Electron microscopic analysis of light radioautographs , 1980, The Journal of comparative neurology.

[31]  Catherine L Nutt,et al.  The Oligodendroglial Lineage Marker OLIG2 Is Universally Expressed in Diffuse Gliomas , 2004, Journal of neuropathology and experimental neurology.

[32]  M. Götz,et al.  Neuronal fate determinants of adult olfactory bulb neurogenesis , 2005, Nature Neuroscience.

[33]  M. Rao.  Multipotent and restricted precursors in the central nervous system , 1999, The Anatomical record.

[34]  J. Fok-Seang,et al.  Evidence for the ventral origin of oligodendrocyte precursors in the rat spinal cord , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[35]  J. E. Vaughn.  An electron microscopic analysis of gliogenesis in rat optic nerves , 2004, Zeitschrift für Zellforschung und Mikroskopische Anatomie.

[36]  M. Götz,et al.  Regionalization and fate specification in neurospheres: the role of Olig2 and Pax6 , 2004, Molecular and Cellular Neuroscience.

[37]  P. Yarowsky,et al.  Astrocytosis and axonal proliferation in the hippocampus of S100b transgenic mice. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Goldman,et al.  Endogenous Progenitors Remyelinate Demyelinated Axons in the Adult CNS , 1997, Neuron.

[39]  Nobuaki Tamamaki,et al.  Radial glia is a progenitor of neocortical neurons in the developing cerebral cortex , 2001, Neuroscience Research.

[40]  A. Chédotal,et al.  Directional Guidance of Oligodendroglial Migration by Class 3 Semaphorins and Netrin-1 , 2002, The Journal of Neuroscience.

[41]  François Guillemot,et al.  Mash1 specifies neurons and oligodendrocytes in the postnatal brain , 2004, The EMBO journal.

[42]  David J. Anderson,et al.  Deregulation of Dorsoventral Patterning by FGF Confers Trilineage Differentiation Capacity on CNS Stem Cells In Vitro , 2003, Neuron.

[43]  J. Trotter,et al.  Cell-Surface Glycoprotein of Oligodendrocyte Progenitors Involved in Migration , 1999, The Journal of Neuroscience.

[44]  David J. Anderson,et al.  The bHLH Transcription Factors OLIG2 and OLIG1 Couple Neuronal and Glial Subtype Specification , 2002, Cell.

[45]  Palma Iannarelli,et al.  Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage , 2006, Nature Neuroscience.

[46]  Ying Liu,et al.  Olig genes are expressed in a heterogeneous population of precursor cells in the developing spinal cord , 2004, Glia.

[47]  D. Rowitch,et al.  Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[48]  W. Blakemore.  Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice , 1972, Journal of neurocytology.

[49]  J. Baudier,et al.  Nuclear expression of S100B in oligodendrocyte progenitor cells correlates with differentiation toward the oligodendroglial lineage and modulates oligodendrocytes maturation , 2004, Molecular and Cellular Neuroscience.

[50]  James E. Goldman,et al.  Multiple Cell Populations in the Early Postnatal Subventricular Zone Take Distinct Migratory Pathways: A Dynamic Study of Glial and Neuronal Progenitor Migration , 2003, The Journal of Neuroscience.

[51]  M. Raff,et al.  A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium , 1983, Nature.

[52]  M. Carpenter.  The Fine Structure of the Nervous System , 1970, Neurology.

[53]  M. Raff,et al.  Visualization of O-2A progenitor cells in developing and adult rat optic nerve by quisqualate-stimulated cobalt uptake , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[54]  I. Cobos,et al.  Monofocal origin of telencephalic oligodendrocytes in the anterior entopeduncular area of the chick embryo. , 2001, Development.

[55]  Fernando Nottebohm,et al.  Proliferation “hot spots” in adult avian ventricular zone reveal radial cell division , 1990, Neuron.

[56]  S. Martinez,et al.  Multiple restricted origin of oligodendrocytes , 1997, Journal of Neuroimmunology.

[57]  V. Gallo,et al.  NG2-expressing cells in the subventricular zone are type C–like cells and contribute to interneuron generation in the postnatal hippocampus , 2004, The Journal of cell biology.

[58]  N. Baumann,et al.  Biology of oligodendrocyte and myelin in the mammalian central nervous system. , 2001, Physiological reviews.

[59]  J. Price,et al.  The generation of neurons and oligodendrocytes from a common precursor cell , 1991, Neuron.

[60]  G. Rougon,et al.  Growth and Fate of PSA-NCAM+ Precursors of the Postnatal Brain , 1998, The Journal of Neuroscience.

[61]  H. Okano,et al.  Asymmetric Inheritance of Radial Glial Fibers by Cortical Neurons , 2001, Neuron.

[62]  J. García-Verdugo,et al.  Cellular Composition and Three-Dimensional Organization of the Subventricular Germinal Zone in the Adult Mammalian Brain , 1997, The Journal of Neuroscience.

[63]  Alan Carleton,et al.  Becoming a new neuron in the adult olfactory bulb , 2003, Nature Neuroscience.

[64]  A. Álvarez-Buylla,et al.  Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[65]  Tao Sun,et al.  Common Developmental Requirement for Olig Function Indicates a Motor Neuron/Oligodendrocyte Connection , 2002, Cell.

[66]  S. Fancy,et al.  Increased expression of Nkx2.2 and Olig2 identifies reactive oligodendrocyte progenitor cells responding to demyelination in the adult CNS , 2004, Molecular and Cellular Neuroscience.

[67]  A. Kakita,et al.  Patterns and Dynamics of SVZ Cell Migration in the Postnatal Forebrain Monitoring Living Progenitors in Slice Preparations , 1999, Neuron.

[68]  H. Varmus,et al.  Basic fibroblast growth factor induces cell migration and proliferation after glia-specific gene transfer in mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[69]  H. Takebayashi,et al.  Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway , 2004, Cell Death and Differentiation.

[70]  Angelo L. Vescovi,et al.  Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis , 2003, Nature.

[71]  W. Carroll,et al.  In situ characterisation of oligodendrocyte progenitor cells in adult mammalian optic nerve , 2002, Journal of neurocytology.

[72]  J. Goldman,et al.  Olig2 Directs Astrocyte and Oligodendrocyte Formation in Postnatal Subventricular Zone Cells , 2005, The Journal of Neuroscience.

[73]  Arturo Alvarez-Buylla,et al.  EGF Converts Transit-Amplifying Neurogenic Precursors in the Adult Brain into Multipotent Stem Cells , 2002, Neuron.

[74]  L. Covarrubias,et al.  The in vivo positional identity gene expression code is not preserved in neural stem cells grown in culture , 2003, The European journal of neuroscience.

[75]  C. Heldin,et al.  Co‐localization of NG2 proteoglycan and PDGF α‐receptor on O2A progenitor cells in the developing rat brain , 1996, Journal of neuroscience research.

[76]  W. Richardson,et al.  A singularity of PDGF alpha-receptor expression in the dorsoventral axis of the neural tube may define the origin of the oligodendrocyte lineage. , 1993, Development.

[77]  W. Richardson,et al.  Oligodendrocyte lineage and the motor neuron connection , 2000, Glia.

[78]  Trevor J Kilpatrick,et al.  Expression of the low‐affinity neurotrophin receptor, p75NTR, is upregulated by oligodendroglial progenitors adjacent to the subventricular zone in response to demyelination , 2004, Glia.

[79]  Arturo Alvarez-Buylla,et al.  A unified hypothesis on the lineage of neural stem cells , 2001, Nature Reviews Neuroscience.

[80]  I. Cobos,et al.  Spatiotemporal development of oligodendrocytes in the embryonic brain , 2000, Journal of neuroscience research.

[81]  M. Raff,et al.  Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. , 2000, Science.

[82]  Daniel A. Lim,et al.  Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain , 1999, Cell.

[83]  M. Sofroniew,et al.  The Predominant Neural Stem Cell Isolated from Postnatal and Adult Forebrain But Not Early Embryonic Forebrain Expresses GFAP , 2003, The Journal of Neuroscience.

[84]  M. Götz,et al.  Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. , 2000, Development.

[85]  Hynek Wichterle,et al.  Direct Evidence for Homotypic, Glia-Independent Neuronal Migration , 1997, Neuron.

[86]  D. Lowenstein,et al.  Prolonged seizures recruit caudal subventricular zone glial progenitors into the injured hippocampus , 2006, Hippocampus.

[87]  L. Puelles,et al.  Oligodendrocytes originate in a restricted zone of the embryonic ventral neural tube defined by DM-20 mRNA expression , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.