Regulation of Olig2 during astroglial differentiation in the subventricular zone of a cuprizone-induced demyelination mouse model

The mammalian subventricular zone (SVZ) is the largest germinative zone of the adult brain. Progenitor cells generated from the SVZ play important roles during the remyelination process. To determine the functional role of Olig2 in regulating astroglial differentiation in the mouse SVZ, we used the cuprizone mouse model to investigate demyelination. We found that cuprizone administration significantly enhanced the expression of Olig2 and increased astroglial differentiation in the SVZ, as compared with control. Moreover, cytoplasmic translocation of Olig2 occurred after demyelination. In vitro studies further revealed that supplementation of culture media with growth factors enhanced the oligodendroglial differentiation of oligodendrocyte progenitor cells (OPCs), whereas serum alone promoted astroglial differentiation and cytoplasmic translocation of Olig2. Additionally, the expression levels of bone morphogenetic proteins 2 and 4 (BMP2 and BMP4) and inhibitor of DNA binding 2 and 4 (Id2 and Id4) were greatly elevated during astroglial differentiation. BMP inhibition by noggin suppressed the astroglial differentiation of OPCs. Our results indicate that Olig2 may serve as a key regulator during the directional differentiation of progenitor cells after demyelination. The BMP signaling pathway may contribute to the cytoplasmic translocation and altered expression of Olig2 during the remyelination process. These findings provide a better understanding of the mechanisms involved in remyelination.

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

[2]  H. Wiendl,et al.  Cytoplasmic translocation of Olig2 in adult glial progenitors marks the generation of reactive astrocytes following autoimmune inflammation , 2006, Experimental Neurology.

[3]  L. Hillered,et al.  Expression of serine/threonine kinase receptors in traumatic brain injury , 1997, Neuroreport.

[4]  W. Gomes,et al.  Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. , 2003, Developmental biology.

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

[6]  M. Mehler,et al.  Bone Morphogenetic Proteins Promote Astroglial Lineage Commitment by Mammalian Subventricular Zone Progenitor Cells , 1996, Neuron.

[7]  T. Kilpatrick,et al.  Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone‐induced demyelination , 2010, Journal of neurochemistry.

[8]  D. Pleasure,et al.  Bone morphogenetic proteins 4, 6, and 7 are up‐regulated in mouse spinal cord during experimental autoimmune encephalomyelitis , 2008, Journal of neuroscience research.

[9]  J. Kessler,et al.  Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation , 2004, Development.

[10]  R. Kamijo,et al.  Purification and identification of a BMP-like factor from bovine serum. , 2006, Biochemical and biophysical research communications.

[11]  C. Wegner,et al.  Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. , 2008, Brain : a journal of neurology.

[12]  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.

[13]  Q. Lu,et al.  The Basic Helix-Loop-Helix Transcription Factor Olig2 Is Critical for Reactive Astrocyte Proliferation after Cortical Injury , 2008, The Journal of Neuroscience.

[14]  K. Sato,et al.  Bone morphogenetic protein receptor expressions in the adult rat brain , 2011, Neuroscience.

[15]  J. Grinspan,et al.  Sending Mixed Signals: Bone Morphogenetic Protein in Myelination and Demyelination , 2009, Journal of neuropathology and experimental neurology.

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

[17]  M. Schachner,et al.  Differential expression of cell fate determinants in neurons and glial cells of adult mouse spinal cord after compression injury , 2005, The European journal of neuroscience.

[18]  M. Mehler,et al.  Combinatorial Profiles of Oligodendrocyte-Selective Classes of Transcriptional Regulators Differentially Modulate Myelin Basic Protein Gene Expression , 2005, The Journal of Neuroscience.

[19]  P. Morell,et al.  The Neurotoxicant, Cuprizone, as a Model to Study Demyelination and Remyelination in the Central Nervous System , 2001, Brain pathology.

[20]  S. Johann,et al.  Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus , 2009, Journal of neuroscience research.

[21]  M. Wiles,et al.  Embryonic stem cell development in a chemically defined medium. , 1999, Experimental cell research.

[22]  M. Mehler,et al.  Bone Morphogenetic Proteins Induce Astroglial Differentiation of Oligodendroglial–Astroglial Progenitor Cells , 1997, The Journal of Neuroscience.

[23]  H. Kurooka,et al.  Nucleo-cytoplasmic Shuttling of Id2, a Negative Regulator of Basic Helix-Loop-Helix Transcription Factors* , 2005, Journal of Biological Chemistry.

[24]  S. Whittemore,et al.  Bone Morphogenetic Protein Signaling and Olig1/2 Interact to Regulate the Differentiation and Maturation of Adult Oligodendrocyte Precursor Cells , 2007, Stem cells.

[25]  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.

[26]  M. Nakafuku,et al.  Dynamic expression of basic helix-loop-helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3 , 2000, Mechanisms of Development.

[27]  Richard Reynolds,et al.  The oligodendrocyte precursor cell in health and disease , 2001, Trends in Neurosciences.

[28]  T. Yamashita,et al.  BMP inhibition enhances axonal growth and functional recovery after spinal cord injury , 2008, Journal of neurochemistry.

[29]  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.

[30]  K. Yone,et al.  Traumatic injury-induced BMP7 expression in the adult rat spinal cord , 2001, Brain Research.

[31]  M. Raff,et al.  Differentiation of a bipotential glial progenitor cell in single cell microculture , 1985, Nature.

[32]  Robin J. M. Franklin,et al.  Why does remyelination fail in multiple sclerosis? , 2002, Nature Reviews Neuroscience.

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

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

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

[36]  T. Kondo,et al.  Nuclear export of OLIG2 in neural stem cells is essential for ciliary neurotrophic factor–induced astrocyte differentiation , 2004, The Journal of cell biology.

[37]  C. Beyer,et al.  Cuprizone effect on myelination, astrogliosis and microglia attraction in the mouse basal ganglia , 2009, Brain Research.

[38]  S. Mikawa,et al.  Bone morphogenetic protein‐4 expression in the adult rat brain , 2006, The Journal of comparative neurology.

[39]  Anna C. Williams,et al.  Astrocytes—Friends or foes in multiple sclerosis? , 2007, Glia.

[40]  He-zuo Lü,et al.  BMP signaling mediates astrocyte differentiation of oligodendrocyte progenitor cells. , 2010, The Tohoku journal of experimental medicine.

[41]  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.

[42]  J. Seylaz,et al.  Distribution of bone morphogenetic protein and bone morphogenetic protein receptor transcripts in the rodent nervous system and up-regulation of bone morphogenetic protein receptor type II in hippocampal dentate gyrus in a rat model of global cerebral ischemia , 2000, Neuroscience.

[43]  David J. Anderson,et al.  The bHLH Transcription Factor Olig2 Promotes Oligodendrocyte Differentiation in Collaboration with Nkx2.2 , 2001, Neuron.

[44]  B. Barres,et al.  A Role for the Helix-Loop-Helix Protein Id2 in the Control of Oligodendrocyte Development , 2001, Neuron.

[45]  M. Mattson,et al.  Evidence that nucleocytoplasmic Olig2 translocation mediates brain‐injury‐induced differentiation of glial precursors to astrocytes , 2007, Journal of neuroscience research.

[46]  M. Sofroniew,et al.  Reactive Astrocytes in Neural Repair and Protection , 2005, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[47]  T. Kilpatrick,et al.  Remyelination Is Altered by Bone Morphogenic Protein Signaling in Demyelinated Lesions , 2011, The Journal of Neuroscience.

[48]  D. Loy,et al.  Endogenous Nkx2.2+/Olig2+ oligodendrocyte precursor cells fail to remyelinate the demyelinated adult rat spinal cord in the absence of astrocytes , 2005, Experimental Neurology.

[49]  Ngan B. Doan,et al.  Reactive Astrocytes Protect Tissue and Preserve Function after Spinal Cord Injury , 2004, The Journal of Neuroscience.

[50]  Jie Peng,et al.  Isolation and culture of rat and mouse oligodendrocyte precursor cells , 2007, Nature Protocols.

[51]  Joanne Chan,et al.  Sonic Hedgehog–Regulated Oligodendrocyte Lineage Genes Encoding bHLH Proteins in the Mammalian Central Nervous System , 2000, Neuron.

[52]  S. Fancy,et al.  Stem cells, progenitors and myelin repair , 2005, Journal of anatomy.

[53]  S. Hauser,et al.  Demyelination in primate autoimmune encephalomyelitis and acute multiple sclerosis lesions: A case for antigen‐specific antibody mediation , 1999, Annals of neurology.

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

[55]  L. Parada,et al.  A crucial role for Olig2 in white matter astrocyte development , 2007, Development.

[56]  J. Hugnot,et al.  NG2 and Olig2 Expression Provides Evidence for Phenotypic Deregulation of Cultured Central Nervous System and Peripheral Nervous System Neural Precursor Cells , 2007, Stem cells.

[57]  Kenji F. Tanaka,et al.  Genetic fate mapping of Olig2 progenitors in the injured adult cerebral cortex reveals preferential differentiation into astrocytes , 2008, Journal of neuroscience research.

[58]  Y. Nabeshima,et al.  The Basic Helix-Loop-Helix Factor Olig2 Is Essential for the Development of Motoneuron and Oligodendrocyte Lineages , 2002, Current Biology.