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David H Rowitch - One of the best experts on this subject based on the ideXlab platform.
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OLIG1 is required for noggin induced neonatal myelin repair
Annals of Neurology, 2017Co-Authors: Jennifer K Sabo, Vivi M Heine, John C Silbereis, Lucas Schirmer, Steven W Levison, David H RowitchAbstract:Objective Neonatal white matter injury (NWMI) is a lesion found in preterm infants that can lead to cerebral palsy. Although antagonists of bone morphogenetic protein (BMP) signaling, such as Noggin, promote oligodendrocyte precursor cell (OPC) production after hypoxic-ischemic (HI) injury, the downstream functional targets are poorly understood. The basic helix-loop-helix protein, oligodendrocyte transcription factor 1 (OLIG1), promotes oligodendrocyte (OL) development and is essential during remyelination in adult mice. Here, we investigated whether OLIG1 function is required downstream of BMP antagonism for response to injury in the neonatal brain. Methods We used wild-type and OLIG1-null mice subjected to neonatal stroke and postnatal neural progenitor cultures, and we analyzed OLIG1 expression in human postmortem samples from neonates that suffered HI encephalopathy (HIE). Results OLIG1-null neonatal mice showed significant hypomyelination after moderate neonatal stroke. Surprisingly, damaged white matter tracts in OLIG1-null mice lacked Olig2+ OPCs, and instead proliferating neuronal precursors and GABAergic interneurons were present. We demonstrate that Noggin-induced OPC production requires OLIG1 function. In postnatal neural progenitors, Noggin governs production of OLs versus interneurons through OLIG1-mediated repression of Dlx1/2 transcription factors. Additionally, we observed that OLIG1 and the BMP signaling effector, phosphorylated SMADs (Sma- and Mad-related proteins) 1, 5, and 8, were elevated in the subventricular zone of human infants with HIE compared to controls. Interpretation These findings indicate that OLIG1 has a critical function in regulation of postnatal neural progenitor cell production in response to Noggin. Ann Neurol 2017;81:560–571
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separated at birth the functional and molecular divergence of OLIG1 and olig2
Nature Reviews Neuroscience, 2012Co-Authors: Dimphna H. Meijer, Charles D Stiles, Michael F Kane, Shwetal Mehta, Hongye Liu, Emily P Harrington, Christopher M Taylor, David H RowitchAbstract:Despite their structural similarities and seemingly coordinated expression patterns, oligodendrocyte transcription factor 1 (OLIG1) and OLIG2 have largely non-overlapping roles in CNS development, brain diseases and neural repair. Here, the authors review the molecular factors that may account for the divergent functions of these proteins.
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the oligodendrocyte lineage genes OLIG1 and olig2 in cns development
Journal of Neurochemistry, 2008Co-Authors: Charles D Stiles, Tao Sun, David H RowitchAbstract:The oligodendrocyte lineage genes OLIG1 and Olig2 encode related bHLH proteins that are co-expressed in neural progenitors. Targeted disruption of these two genes sheds light on the ontogeny of oligodendroglia and genetic requirements for their development from multipotent CNS progenitors. Olig2 is required for oligodendrocyte and motor neuron specification in the spinal cord. OLIG1 has roles in development and maturation of oligodendrocytes, evident especially within the brain. Both Olig genes contribute to neural pattern formation. Neither Olig gene is required for astrocytes. These findings, together with fate mapping of Olig-expressing cells, challenge the notion that oligodendrocytes arise from a glial-restricted precursor. Rather, they indicate that oligodendrocytes are derived from Olig-specified progenitors that give rise also to neurons.
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expression pattern of the transcription factor olig2 in response to brain injuries implications for neuronal repair
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Annalisa Buffo, Milan R Vosko, Dilek Erturk, Gerhard F Hamann, Mathias Jucker, David H Rowitch, Magdalena GötzAbstract:Despite the presence of neural stem cells and ongoing neurogenesis in some regions of the adult mammalian brain, neurons are not replaced in most brain regions after injury. With the aim to unravel factors contributing to the failure of neurogenesis in the injured cerebral cortex, we examined the expression of cell fate determinants after acute brain injuries, such as stab wound or focal ischemia, and in a model of chronic amyloid deposition. Although none of the neurogenic factors, such as Pax6, Mash1, Ngn2, was detected in the injured parenchyma, we observed a strong up-regulation of the bHLH transcription factor Olig2, but not OLIG1, upon acute and chronic injury. To examine the function of Olig2 in brain lesion, we injected retroviral vectors containing a dominant negative form of Olig2 into the lesioned cortex 2 days after a stab wound. Antagonizing Olig2 function resulted in a significant number of infected cells generating immature neurons that were not observed after injection of the control virus. These data, therefore, imply Olig2 as a repressor of neurogenesis in cells reacting to brain injury and open innovative perspectives toward evoking endogenous neuronal repair.
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Olig2 expression, GFAP, p53 and 1p loss analysis contribute to glioma subclassification
Neuropathology and applied neurobiology, 2005Co-Authors: Karima Mokhtari, David H Rowitch, Sophie Paris, Lucinda Aguirre-cruz, N. Privat, Emmanuelle Crinière, Yannick Marie, Jean-jacques Hauw, M. Kujas, Khê Hoang-xuanAbstract:The expression of Olig2, a basic helix–loop–helix (bHLH) transcription factor involved in oligodendroglial specification, was investigated by immunohistochemistry in a series of 146 tumours and control samples. Olig2 expression was restricted to glial tumours and nontumoral oligodendrocytes. It was higher in oligodendrogliomas as compared to astrocytomas and oligoastrocytomas, and in grade III as compared to grade II tumours. Olig 2 was absent or weakly expressed in glioblastoma (GBM), whereas strong expression was found in the oligodendroglial foci of GBM with oligodendroglial component (GBMO). Double labelling was performed on a subset of the most typical tumours, according to the WHO classification. It showed a mutual exclusion, at cell level, of Olig2 and GFAP expression. In pure oligodendrogliomas, tumour cells were Olig2+/GFAP–. In contrast, two main tumour populations, Olig2+/GFAP– and Olig2–/GFAP+, were found in both oligoastrocytomas and astrocytomas. Based on these data from selected samples, two separate entities can be established, corresponding to ‘pure oligodendrogliomas’ and ‘astrocytomas and oligoastrocytomas’. The relevance of this subdivision is further supported by the association with 1p loss and a trend to better survival for pure oligodendrogliomas and with p53 expression and a trend to shorter survival for astrocytomas and oligoastrocytomas. Combined testing of Olig2, 1p status, GFAP and p53 expression may therefore be helpful in refining current classification and providing more homogeneous sets of gliomas for clinical studies.
Michael Wegner - One of the best experts on this subject based on the ideXlab platform.
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Elevated In Vivo Levels of a Single Transcription Factor Directly Convert Satellite Glia into Oligodendrocyte-like Cells
PLoS Genetics, 2015Co-Authors: Matthias Weider, Amélie Wegener, Christian Schmitt, Melanie Küspert, Simone Hillgärtner, Michael R Bösl, Irm Hermans-borgmeyer, Brahim Nait-oumesmar, Michael WegnerAbstract:Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the transcription factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, OLIG1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dor-sal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.
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olig2 regulates sox10 expression in oligodendrocyte precursors through an evolutionary conserved distal enhancer
Nucleic Acids Research, 2011Co-Authors: Melanie Küspert, Michael R Bösl, Alexander Hammer, Michael WegnerAbstract:The HMG-domain transcription factor Sox10 is expressed throughout oligodendrocyte development and is an important component of the transcriptional regulatory network in these myelin-forming CNS glia. Of the known Sox10 regulatory regions, only the evolutionary conserved U2 enhancer in the distal 5′-flank of the Sox10 gene exhibits oligodendroglial activity. We found that U2 was active in oligodendrocyte precursors, but not in mature oligodendrocytes. U2 activity also did not mediate the initial Sox10 induction after specification arguing that Sox10 expression during oligodendroglial development depends on the activity of multiple regulatory regions. The oligodendroglial bHLH transcription factor Olig2, but not the closely related OLIG1 efficiently activated the U2 enhancer. Olig2 bound U2 directly at several sites including a highly conserved one in the U2 core. Inactivation of this site abolished the oligodendroglial activity of U2 in vivo. In contrast to Olig2, the homeodomain transcription factor Nkx6.2 repressed U2 activity. Repression may involve recruitment of Nkx6.2 to U2 and inactivation of Olig2 and other activators by protein–protein interactions. Considering the selective expression of Nkx6.2 at the time of specification and in differentiated oligodendrocytes, Nkx6.2 may be involved in limiting U2 activity to the precursor stage during oligodendrocyte development.
Charles D Stiles - One of the best experts on this subject based on the ideXlab platform.
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separated at birth the functional and molecular divergence of OLIG1 and olig2
Nature Reviews Neuroscience, 2012Co-Authors: Dimphna H. Meijer, Charles D Stiles, Michael F Kane, Shwetal Mehta, Hongye Liu, Emily P Harrington, Christopher M Taylor, David H RowitchAbstract:Despite their structural similarities and seemingly coordinated expression patterns, oligodendrocyte transcription factor 1 (OLIG1) and OLIG2 have largely non-overlapping roles in CNS development, brain diseases and neural repair. Here, the authors review the molecular factors that may account for the divergent functions of these proteins.
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the oligodendrocyte lineage genes OLIG1 and olig2 in cns development
Journal of Neurochemistry, 2008Co-Authors: Charles D Stiles, Tao Sun, David H RowitchAbstract:The oligodendrocyte lineage genes OLIG1 and Olig2 encode related bHLH proteins that are co-expressed in neural progenitors. Targeted disruption of these two genes sheds light on the ontogeny of oligodendroglia and genetic requirements for their development from multipotent CNS progenitors. Olig2 is required for oligodendrocyte and motor neuron specification in the spinal cord. OLIG1 has roles in development and maturation of oligodendrocytes, evident especially within the brain. Both Olig genes contribute to neural pattern formation. Neither Olig gene is required for astrocytes. These findings, together with fate mapping of Olig-expressing cells, challenge the notion that oligodendrocytes arise from a glial-restricted precursor. Rather, they indicate that oligodendrocytes are derived from Olig-specified progenitors that give rise also to neurons.
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bHLH transcription factor OLIG1 is required to repair demyelinated lesions in the CNS.
Science (New York N.Y.), 2004Co-Authors: Heather A. Arnett, Robin J.m. Franklin, Stephen P.j. Fancy, Chao Zhao, David H Rowitch, John A. Alberta, Sovann Kaing, Sheila R. Plant, Cedric S. Raine, Charles D StilesAbstract:OLIG1 and Olig2 are closely related basic helix-loop-helix (bHLH) transcription factors that are expressed in myelinating oligodendrocytes and their progenitor cells in the developing central nervous system (CNS). Olig2 is necessary for the specification of oligodendrocytes, but the biological functions of OLIG1 during oligodendrocyte lineage development are poorly understood. We show here that OLIG1 function in mice is required not to develop the brain but to repair it. Specifically, we demonstrate a genetic requirement for OLIG1 in repairing the types of lesions that occur in patients with multiple sclerosis.
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The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas.
Journal of neuropathology and experimental neurology, 2004Co-Authors: Keith L. Ligon, Charles D Stiles, John A. Alberta, Alvin T. Kho, Jennifer Weiss, Mary R. Kwaan, Catherine L. Nutt, David N. Louis, David H RowitchAbstract:Astrocytomas, oligodendrogliomas, and oligoastrocytomas, collectively referred to as diffuse gliomas, are the most common primary brain tumors. These tumors are classified by histologic similarity to differentiated astrocytes and oligodendrocytes, but this approach has major limitations in guiding modern treatment and research. Lineage markers represent a potentially useful adjunct to morphologic classification. The murine bHLH transcription factors OLIG1 and Olig2 are expressed in neural progenitors and oligodendroglia and are essential for oligodendrocyte development. High OLIG expression alone has been proposed to distinguish oligodendrogliomas from astrocytomas, so we critically evaluated OLIG2 as a marker by immunohistochemical and oligonucleotide microarray analysis. OLIG2 protein is faithfully restricted to normal oligodendroglia and their progenitors in human brain. Immunohistochemical analysis of 180 primary, metastatic, and non-neural human tumors shows OLIG2 is highly expressed in all diffuse gliomas. Immunohistochemistry and microarray analyses demonstrate higher OLIG2 in anaplastic oligodendrogliomas versus glioblastomas, which are heterogeneous with respect to OLIG2 levels. OLIG2 protein expression is present but inconsistent and generally lower in most other brain tumors and is absent in non-neuroectodermal tumors. Overall, OLIG2 is a useful marker of diffuse gliomas as a class. However, expression heterogeneity of OLIG2 in astrocytomas precludes immunohistochemical classification of individual gliomas by OLIG2 alone.
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basic helix loop helix factors in cortical development
Neuron, 2003Co-Authors: Sarah E Ross, Michael E Greenberg, Charles D StilesAbstract:Transcription factors with bHLH motifs modulate critical events in the development of the mammalian neocortex. Multipotent cortical progenitors are maintained in a proliferative state by bHLH factors from the Id and Hes families. The transition from proliferation to neurogenesis involves a coordinate increase in the activity of proneural bHLH factors (Mash1, Neurogenin1, and Neurogenin2) and a decrease in the activity of Hes and Id factors. As development proceeds, inhibition of proneural bHLH factors in cortical progenitors promotes the formation of astrocytes. Finally, the formation of oligodendrocytes is triggered by an increase in the activity of bHLH factors OLIG1 and Olig2 that may be coupled with a decrease in Id activity. Thus, bHLH factors have key roles in corticogenesis, affecting the timing of differentiation and the specification of cell fate.
William D. Richardson - One of the best experts on this subject based on the ideXlab platform.
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Evolution of the CNS myelin gene regulatory program.
Brain Research, 2016Co-Authors: William D. RichardsonAbstract:Myelin is a specialized subcellular structure that evolved uniquely in vertebrates. A myelinated axon conducts action potentials many times faster than an unmyelinated axon of the same diameter; for the same conduction speed, the unmyelinated axon would need a much larger diameter and volume than its myelinated counterpart. Hence myelin speeds information transfer and saves space, allowing the evolution of a powerful yet portable brain. Myelination in the central nervous system (CNS) is controlled by a gene regulatory program that features a number of master transcriptional regulators including OLIG1, Olig2 and Myrf. Olig family genes evolved from a single ancestral gene in non-chordates. Olig2, which executes multiple functions with regard to oligodendrocyte identity and development in vertebrates, might have evolved functional versatility through post-translational modification, especially phosphorylation, as illustrated by its evolutionarily conserved serine/threonine phospho-acceptor sites and its accumulation of serine residues during more recent stages of vertebrate evolution. OLIG1, derived from a duplicated copy of Olig2 in early bony fish, is involved in oligodendrocyte development and is critical to remyelination in bony vertebrates, but is lost in birds. The origin of Myrf orthologs might be the result of DNA integration between an invading phage or bacterium and an early protist, producing a fusion protein capable of self-cleavage and DNA binding. Myrf seems to have adopted new functions in early vertebrates - initiation of the CNS myelination program as well as the maintenance of mature oligodendrocyte identity and myelin structure - by developing new ways to interact with DNA motifs specific to myelin genes. This article is part of a Special Issue entitled SI: Myelin Evolution.
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New OLIG1 null mice confirm a non-essential role for OLIG1 in oligodendrocyte development
BMC neuroscience, 2014Co-Authors: Joana Paes De Faria, Nicoletta Kessaris, Paul Andrew, William D. RichardsonAbstract:Background OLIG1 and Olig2, encoding closely related basic helix-loop-helix transcription factors, were originally identified in screens for glial-specific genes. OLIG1 and Olig2 are both expressed in restricted parts of the neuroepithelium of the embryonic spinal cord and telencephalon and subsequently in oligodendrocyte lineage cells throughout life. In the spinal cord, Olig2 plays a crucial role in the development of oligodendrocytes and motor neurons, and both cell types are lost from Olig2 null mutant mice. The role of OLIG1 has been more cryptic. It was initially reported that OLIG1 null mice (with a Cre-Pgk-Neo cassette at the OLIG1 locus) have a mild developmental phenotype characterized by a slight delay in oligodendrocyte differentiation. However, a subsequent study of the same line following removal of Pgk-Neo (leaving OLIG1-Cre) found severe disruption of oligodendrocyte production, myelination failure and early postnatal lethality. A plausible explanation was proposed, that the highly expressed Pgk-Neo cassette in the original line might have up-regulated the neighbouring Olig2 gene, compensating for loss of OLIG1. However, this was not tested, so the importance of OLIG1 for oligodendrocyte development has remained unclear.
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OLIG1 and sox10 interact synergistically to drive myelin basic protein transcription in oligodendrocytes
The Journal of Neuroscience, 2007Co-Authors: Hazel K Smith, William D. RichardsonAbstract:The oligodendrocyte lineage genes (OLIG1/2), encoding basic helix-loop-helix transcription factors, were first identified in screens for master regulators of oligodendrocyte development. OLIG1 is important for differentiation of oligodendrocyte precursors into myelin-forming oligodendrocytes during development and is thought to play a crucial role in remyelination during multiple sclerosis. However, it is still unclear how OLIG1 interacts with its transcriptional cofactors and DNA targets. OLIG1 was reportedly restricted to mammals, but we demonstrate here that zebrafish and other teleosts also possess an OLIG1 homolog. In zebrafish, as in mammals, OLIG1 is expressed in the oligodendrocyte lineage. OLIG1 associates physically with another myelin-associated transcription factor, Sox10, and the OLIG1/Sox10 complex activates mbp (myelin basic protein) transcription via conserved DNA sequence motifs in the mbp promoter region. In contrast, Olig2 does not bind to Sox10 in zebrafish, although both OLIG1 and OLIG2 bind SOX10 in mouse.
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oligodendrocyte development in the spinal cord and telencephalon common themes and new perspectives
International Journal of Developmental Neuroscience, 2001Co-Authors: Rachel H Woodruff, Charles D Stiles, David H Rowitch, Nicoletta Tekkikessaris, William D. RichardsonAbstract:There are clear parallels between oligodendrocyte development in the spinal cord and forebrain. However, there is new evidence that in both of these regions oligodendrocyte lineage development may be more complex than we earlier thought. This stems from the recent identification of three new transcription factor genes, OLIG1, Olig2 and Sox10, that are expressed from the early stages of oligodendrocyte lineage development. In this article, we highlight the common themes underlying specification and early development of oligodendrocytes in the spinal cord and telencephalon. Then, we discuss recent studies of Sox10 and the Olig genes and their implications for oligodendrocyte specification. We conclude that although the mechanisms of oligodendrogenesis appear to be fundamentally similar at different rostro-caudal levels of the neuraxis, there are still many unanswered questions about the details of oligodendrocyte specification.
Satoshi Miyashita - One of the best experts on this subject based on the ideXlab platform.
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Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum
Nature communications, 2014Co-Authors: Yusuke Seto, Shinichiro Taya, Yukiko U. Inoue, Takayoshi Inoue, Norihisa Masuyama, Tomoya Nakatani, Minoru Kumai, Yasuko Minaki, Akiko Hamaguchi, Satoshi MiyashitaAbstract:In the cerebellum, all GABAergic neurons are generated from the Ptf1a-expressing ventricular zone (Ptf1a domain). However, the machinery to produce different types of GABAergic neurons remains elusive. Here we show temporal regulation of distinct GABAergic neuron progenitors in the cerebellum. Within the Ptf1a domain at early stages, we find two subpopulations; dorsally and ventrally located progenitors that express Olig2 and Gsx1, respectively. Lineage tracing reveals the former are exclusively Purkinje cell progenitors (PCPs) and the latter Pax2-positive interneuron progenitors (PIPs). As development proceeds, PCPs gradually become PIPs starting from ventral to dorsal. In gain- and loss-of-function mutants for Gsx1 and OLIG1/2, we observe abnormal transitioning from PCPs to PIPs at inappropriate developmental stages. Our findings suggest that the temporal identity transition of cerebellar GABAergic neuron progenitors from PCPs to PIPs is negatively regulated by Olig2 and positively by Gsx1, and contributes to understanding temporal control of neuronal progenitor identities.
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Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum
Nature Communications, 2014Co-Authors: Yusuke Seto, Shinichiro Taya, Yukiko U. Inoue, Takayoshi Inoue, Norihisa Masuyama, Tomoya Nakatani, Minoru Kumai, Yasuko Minaki, Akiko Hamaguchi, Satoshi MiyashitaAbstract:GABAergic neuron progenitors in the cerebellum give rise to Purkinje cells and GABAergic interneurons. Here the authors show that the transcription factors Olig2 and Gsx1 regulate an identity transition from Purkinje cell progenitors to interneuron progenitors during mouse development. In the cerebellum, all GABAergic neurons are generated from the Ptf1a-expressing ventricular zone (Ptf1a domain). However, the machinery to produce different types of GABAergic neurons remains elusive. Here we show temporal regulation of distinct GABAergic neuron progenitors in the cerebellum. Within the Ptf1a domain at early stages, we find two subpopulations; dorsally and ventrally located progenitors that express Olig2 and Gsx1, respectively. Lineage tracing reveals the former are exclusively Purkinje cell progenitors (PCPs) and the latter Pax2-positive interneuron progenitors (PIPs). As development proceeds, PCPs gradually become PIPs starting from ventral to dorsal. In gain- and loss-of-function mutants for Gsx1 and OLIG1/2 , we observe abnormal transitioning from PCPs to PIPs at inappropriate developmental stages. Our findings suggest that the temporal identity transition of cerebellar GABAergic neuron progenitors from PCPs to PIPs is negatively regulated by Olig2 and positively by Gsx1, and contributes to understanding temporal control of neuronal progenitor identities.
