Skip to main content
SpringerLink
Log in

Plasticity of the myelination genomic fabric

  • Original Paper
  • Published:
Molecular Genetics and Genomics Aims and scope Submit manuscript

Abstract

This study aimed to quantify the influence of the astrocyte proximity on myelination genomic fabric (MYE) of oligodendrocytes, defined as the most interconnected and stably expressed gene web responsible for myelination. Such quantitation is important to evaluate whether astrocyte signaling may contribute to demyelination when impaired and remyelination when properly restored. For this, we compared changes in the gene expression profiles of immortalized precursor oligodendrocytes (Oli-neu), stimulated to differentiate by the proximity of nontouching astrocytes or treatment with db-cAMP. In a previous paper, we reported that the astrocyte proximity upregulated or turned-on a large number of myelination genes and substantially enriched the Ca2+-signaling and cytokine receptor regulatory networks of MYE in Oli-neu cells. Here, we introduce the “transcriptomic distance” to evaluate fabric remodeling and “pair-wise relevance” to identify the most influential gene pairs. Together with the prominence gene analysis used to select and rank the fabric genes, these novel analytical tools provide a comprehensively quantitative view of the physio/pathological transformations of the transcriptomic programs of myelinating cells. Applied to our data, the analyses revealed not only that the astrocyte neighborhood is a substantially more powerful regulator of myelination than the differentiating treatment but also the molecular mechanisms of the two differentiating paradigms are different. By inducing a profound remodeling of MYE and regulatory transcriptomic networks, the astrocyte–oligodendrocyte intercommunication may be considered as a major player in both pathophysiology and therapy of neurodegenerative diseases related to myelination.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Aguirre A, Dupree JL, Mangin JM, Gallo V (2007) A functional role for EGFR signaling in myelination and remyelination. Nat Neurosci 10(2007):990–1002

    Article  PubMed  CAS  Google Scholar 

  • Bajo-Grañeras R, Sanchez D, Gutierrez G, González C, Do Carmo S, Rassart E, Ganfornina MD (2011) Apolipoprotein D alters the early transcriptional response to oxidative stress in the adult cerebellum. J Neurochem 117:949–960

    Article  PubMed  Google Scholar 

  • Banerjee S, Oldridge D, Poptsova M, Hussain WM, Chakravarty D, Demichelis F (2011) A computational framework discovers new copy number variants with functional importance. PLoS One 6(3):e17539

    Article  PubMed  CAS  Google Scholar 

  • Bondurand N, Girard M, Pingault V, Lemort N, Dubourg O, Goossens M (2001) Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10. Hum Mol Genet 10:2783–2795

    Article  PubMed  CAS  Google Scholar 

  • Braitch M, Constantinescu CS (2010). The role of osteopontin in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). Inflamm Allergy Drug Targets. 9:249–256 (Review)

    Google Scholar 

  • Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264–278

    Article  PubMed  CAS  Google Scholar 

  • Ceruti S, Viganò F, Boda E, Ferrario S, Magni G, Boccazzi M, Rosa P, Buffo A, Abbracchio MP (2011) Expression of the new P2Y-like receptor GPR17 during oligodendrocyte precursor cell maturation regulates sensitivity to ATP-induced death. Glia 59:363–378

    Article  PubMed  Google Scholar 

  • Chen M, Nemechek NM, Mema E, Wang J, Weinstein LS (2011) Effects of deficiency of the G protein G(s)alpha on energy and glucose homeostasis. Eur J Pharmacol 660:119–124

    Article  PubMed  CAS  Google Scholar 

  • Degletagne C, Keime C, Rey B, de Dinechin M, Forcheron F, Chuchana P, Jouventin P, Gautier C, Duchamp C (2010) Transcriptome analysis in non-model species: a new method for the analysis of heterologous hybridization on microarrays. BMC Genomics 11:344

    Article  PubMed  Google Scholar 

  • Demarque M, Spitzer NC (2012) Neurotransmitter phenotype plasticity: An unexpected mechanism in the toolbox of network activity homeostasis. Dev Neurobiol 72(1):22–32

    Article  PubMed  CAS  Google Scholar 

  • Draghici S (2003) Data analysis tools for DNA microarrays. Chapman & Hall/CRC, Boca Raton, London, New York, Washington, pp 264–276

  • Dugas JC, Tai YC, Speed TP, Ngai J, Barres BA (2006) Functional genomic analysis of oligodendrocyte differentiation. J Neurosci 26(43):10967–10983

    Article  PubMed  CAS  Google Scholar 

  • Easterday MC, Dougherty JD, Jackson RL, Ou J, Nakano I, Paucar AA, Roobini B, Dianati M, Irvin DK, Weissman IL, Terskikh AV, Geschwind DH, Kornblum HI (2003) Neural progenitor genes. Germinal zone expression and analysis of genetic overlap in stem cell populations. Dev Biol 264:309–322

    Article  PubMed  CAS  Google Scholar 

  • Emery B, Agalliu D, Cahoy JD, Watkins TA, Dugas JC, Mulinyawe SB, Ibrahim A, Ligon KL, Rowitch DH, Barres BA (2009) Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell 138:172–185

    Article  PubMed  CAS  Google Scholar 

  • Fields RD (2005) Myelination: an overlooked mechanism of synaptic plasticity? Neuroscientist 11:528–531

    Article  PubMed  Google Scholar 

  • Fields RD (2008) White matter in learning, cognition and psychiatric disorders. Trends Neurosci 31:361–370

    Article  PubMed  CAS  Google Scholar 

  • Finzsch M, Stolt CC, Lommes P, Wegner M (2008) Sox9 and Sox10 influence survival and migration of oligodendrocyte precursors in the spinal cord by regulating PDGF receptor alpha expression. Development 135(4):637–646

    Article  PubMed  CAS  Google Scholar 

  • Fitzner D, Schneider A, Kippert A, Möbius W, Willig KI, Hell SW, Bunt G, Gaus K, Simons M (2006) Myelin basic protein-dependent plasma membrane reorganization in the formation of myelin. EMBO J 25:5037–5048

    Article  PubMed  CAS  Google Scholar 

  • Garbay B, Bauxis-Lagrave S, Boiron-Sargueil F, Elson G, Cassagne C (1997) Acetyl-CoA carboxylase gene expression in the developing mouse brain. Comparison with other genes involved in lipid biosynthesis. Brain Res Dev Brain Res 98:97–203

    Article  Google Scholar 

  • Garbay B, Boiron-Sargueil F, Shy M, Chbihi T, Jiang H, Kamholz J, Cassagne C (1998) Regulation of oleoyl-CoA synthesis in the peripheral nervous system: demonstration of a link with myelin synthesis. J Neurochem 71:1719–1726

    Article  PubMed  CAS  Google Scholar 

  • Gokhan S, Marin-Husstege M, Yung SY, Fontanez D, Casaccia-Bonnefil P, Mehler MF (2005) Combinatorial profiles of oligodendrocyte-selective classes of transcriptional regulators differentially modulate myelin basic protein gene expression. J Neurosci 25:8311–8321

    Article  PubMed  CAS  Google Scholar 

  • Hancock V, Vejborg RM, Klemm P (2010) Functional genomics of probiotic Escherichia coli Nissle 1917 and 83972, and UPEC strain CFT073: comparison of transcriptomes, growth and biofilm formation. Mol Genet Genomics 284(6):437–454

    Article  PubMed  CAS  Google Scholar 

  • Iacobas S, Iacobas DA (2011) Astrocyte proximity modulates the myelination gene fabric of oligodendrocytes. Neuron Glia Biol 6:157–169

    Article  Google Scholar 

  • Iacobas DA, Iacobas S, Li WE, Zoidl G, Dermietzel R, Spray DC (2005a) Genes controlling multiple functional pathways are transcriptionally regulated in connexin43 null mouse heart. Physiol Genomics 20:211–223

    PubMed  CAS  Google Scholar 

  • Iacobas DA, Iacobas S, Urban-Maldonado M, Spray DC (2005b) Sensitivity of the brain transcriptome to connexin ablation, Biochimica et Biofisica Acta 1711:183–196 (Review)

    Google Scholar 

  • Iacobas DA, Suadicani SO, Spray DC, Scemes E (2006) A stochastic 2D model of intercellular Ca2+ wave spread in glia. Biophys J 90(1):24–41

    Article  PubMed  CAS  Google Scholar 

  • Iacobas DA, Iacobas S, Spray DC (2007a) Connexin43 and the brain transcriptome of the newborn mice. Genomics 89(1):113–123

    Article  PubMed  CAS  Google Scholar 

  • Iacobas DA, Iacobas S, Spray DC (2007b) Connexin-dependent transcellular transcriptomic networks in mouse brain. Prog Biophys Mol Biol. 94(1–2):168–184 (Review)

    Google Scholar 

  • Iacobas DA, Iacobas S, Urban-Maldonado M, Scemes E, Spray DC (2008) Similar transcriptomic alterations in Cx43 knock-down and knock-out astrocytes. Cell Commun Adhes 15(1):195–206

    Article  PubMed  CAS  Google Scholar 

  • Iacobas DA, Iacobas S, Haddad GG (2010a) Heart rhythm genomic fabric in hypoxia. Biochem Biophys Res Commun 391:1769–1774

    Article  PubMed  CAS  Google Scholar 

  • Iacobas, S. Iacobas, N. Thomas, Spray DC (2010a) Sex-dependent gene regulatory networks of the heart rhythm. Funct Integr Genomics 10:73–86

  • Joubert L, Foucault I, Sagot Y, Bernasconi L, Duval F, Alliod C, Frossard MJ, Pescini Gobert R, Curchod ML, Salvat C, Nichols A, Pouly S, Rommel C, Roach A, van Hooft Huijsduijnen R (2010) Chemical inducers and transcriptional markers of oligodendrocyte differentiation. J Neurosci Res 88:2546–2557

    PubMed  CAS  Google Scholar 

  • Jung M, Krämer E, Grzenkowski M, Tang K, Blakemore W, Aguzzi A, Khazaie K, Chlichlia K, von Blankenfeld G, Kettenmann H et al (1995) Lines of murine oligodendroglial precursor cells immortalized by an activated neu tyrosine kinase show distinct degrees of interaction with axons in vitro and in vivo. Eur J Neurosci 7:1245–1265

    Article  PubMed  CAS  Google Scholar 

  • Kaya F, Belin S, Bourgeois P, Micaleff J, Blin O, Fontés M (2007) Ascorbic acid inhibits PMP22 expression by reducing cAMP levels. Neuromuscul Disord 17:248–253

    Article  PubMed  Google Scholar 

  • Kippert A, Trajkovic K, Fitzner D, Opitz L, Simons M (2008) Identification of Tmem10/Opalin as a novel marker for oligodendrocytes using gene expression profiling. BMC Neurosci 9:40

    Article  PubMed  Google Scholar 

  • Kramer EM, Schardt A, Nave KA (2001) Membrane traffic in myelinating oligodendrocytes. Microsc Res Tech 52:656–671

    Article  PubMed  CAS  Google Scholar 

  • Lachtermacher S, Esporcatte BL, da Silva de Azevedo Fortes F, Rocha NN, Montalvão F, Costa PC, Belem L, Rabischoffisky A, Faria Neto HC, Vasconcellos R, Iacobas DA, Iacobas S, Spray DC, Thomas NM, Goldenberg RC, Campos de Carvalho AC (2011) Functional and transcriptomic recovery of infarcted mouse myocardium treated with bone marrow mononuclear cells. Stem Cell Rev (Epub ahead of print)

  • Lau P, Verrier JD, Nielsen JA, Johnson KR, Notterpek L, Hudson LD (2008) Identification of dynamically regulated microRNA and mRNA networks in developing oligodendrocytes. J Neurosci 28(45):11720–11730

    Article  PubMed  CAS  Google Scholar 

  • Lee WP, Tzou WS (2009) Computational methods for discovering gene networks from expression data. Brief Bioinform 10:408–423

    PubMed  CAS  Google Scholar 

  • Li H, Lu Y, Smith HK, Richardson WD (2007) Olig1 and Sox10 interact synergistically to drive myelin basic protein transcription in oligodendrocytes. J Neurosci 27:14375–14382

    Article  PubMed  CAS  Google Scholar 

  • Mizuno T, Zhang G, Takeuchi H, Kawanokuchi J, Wang J, Sonobe Y, Jin S, Takada N, Komatsu Y, Suzumura A (2008) Interferon-gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-gamma receptor and AMPA GluR1 receptor. FASEB J 22:1797–1806

    Article  PubMed  CAS  Google Scholar 

  • Moe KT, Chung JW, Cho YI, Moon JK, Ku JH, Jung JK, Lee J, Park YJ (2011) Sequence information on simple sequence repeats and single nucleotide polymorphisms through transcriptome analysis of mungbean. J Integr Plant Biol 53(1):63–73

    Article  PubMed  CAS  Google Scholar 

  • Nash B, Ioannidou K, Barnett SC (2011a) Astrocyte phenotypes and their relationship to myelination. J Anat 219(1):44–52. doi:10.1111/j.1469-7580.2010.01330.x

    Article  PubMed  Google Scholar 

  • Nash B, Thomson CE, Linington C, Arthur AT, McClure JD, McBride MW, Barnett SC (2011b) Functional duality of astrocytes in myelination. J Neurosci 31(37):13028–13038

    Article  PubMed  CAS  Google Scholar 

  • Newberna J, Birchmeier C (2010) Nrg1/ErbB signaling networks in Schwann cell development and myelination. Semin Cell Dev Biol 21:922–928 (Review)

    Article  Google Scholar 

  • Nielsen JA, Maric D, Lau P, Barker JL, Hudson LD (2006) Identification of a novel oligodendrocyte cell adhesion protein using gene expression profiling. J Neurosci 26(39):9881–9891

    Article  PubMed  CAS  Google Scholar 

  • Orthmann-Murphy JL, Abrams CK, Scherer SS (2008) Gap junctions couple astrocytes and oligodendrocytes. J Mol Neurosci 35:101–116 (Review)

    Google Scholar 

  • Palacios N, Sánchez-Franco F, Fernández M, Sánchez I, Villuendas G, Cacicedo L (2007) Opposite effects of two PKA inhibitors on cAMP inhibition of IGF-I-induced oligodendrocyte development: a problem of unspecificity? Brain Res 1178:1–11

    Article  PubMed  CAS  Google Scholar 

  • Pingault V, Bondurand N, Le Caignec C, Tardieu S, Lemort N, Dubourg O, Le Guern E, Goossens M, Boespflug-Tanguy O et al (2001) The SOX10 transcription factor: evaluation as a candidate gene for central and peripheral hereditary myelin disorders. J Neurol 248:496–499

    Article  PubMed  CAS  Google Scholar 

  • Raser JM, O’Shea EK (2005) Noise in gene expression: origins, consequences, and control. Science 309:2010–2013

    Article  PubMed  CAS  Google Scholar 

  • Rowe DD, Leonardo CC, Hall AA, Shahaduzzaman MD, Collier LA, Willing AE, Pennypacker KR (2010) Cord blood administration induces oligodendrocyte survival through alterations in gene expression. Brain Res 1366:172–188

    Article  PubMed  CAS  Google Scholar 

  • Salzer JL (2003) Polarized domains of myelinated axons. Neuron 40(2):297–318 (Review)

    Google Scholar 

  • Schaeren-Wiemers N, Schaefer C, Valenzuela DM, Yancopoulos GD, Schwab ME (1995) Identification of new oligodendrocyte- and myelin-specific genes by a differential screening approach. J Neurochem 65:10–22

    Article  PubMed  CAS  Google Scholar 

  • Soares MB, Lima RS, Souza BS, Vasconcelos JF, Rocha LL, Dos Santos RR, Iacobas S, Goldenberg RC, Lisanti MP, Iacobas DA, Tanowitz HB, Spray DC, de Campos Carvalho AC (2011) Reversion of gene expression alterations in hearts of mice with chronic chagasic cardiomyopathy after transplantation of bone marrow cells. Cell Cycle 10:1448–1455

    Article  PubMed  CAS  Google Scholar 

  • Spray DC, Iacobas DA (2007) Organizational principles of the connexin-related brain transcriptome. J Membr Biol 218(1–3):39–47

    Article  PubMed  CAS  Google Scholar 

  • Stolt CC, Rehberg S, Ader M, Lommes P, Riethmacher D, Schachner M, Bartsch U, Wegner M (2002) Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10. Genes Dev 16:165–170

    Google Scholar 

  • Swiss VA, Nguyen T, Dugas J, Ibrahim A, Barres B, Androulakis IP, Casaccia P (2011) Identification of a gene regulatory network necessary for the initiation of oligodendrocyte differentiation. PLoS One 6:e18088

    Article  PubMed  CAS  Google Scholar 

  • Takada N, Kucenas S, Appel B (2010) Sox10 is necessary for oligodendrocyte survival following axon wrapping. Glia 58:996–1006

    PubMed  Google Scholar 

  • Trapp BD, Kidd GJ (2004) Structure of the myelinated axon. Elsevier, San Diego

    Google Scholar 

  • Ulrich R, Kalkuhl A, Deschl U, Baumgärtner W (2010) Machine learning approach identifies new pathways associated with demyelination in a viral model of multiple sclerosis. J Cell Mol Med 14:434–448

    Article  PubMed  CAS  Google Scholar 

  • Wakatsuki S, Yumoto N, Komatsu K, Araki T, Sehara-Fujisawa A (2009) Roles of meltrin-beta/ADAM19 in progression of Schwann cell differentiation and myelination during sciatic nerve regeneration. J Biol Chem 284:2957–2966

    Article  PubMed  CAS  Google Scholar 

  • Wake H, Lee PR, Fields RD (2011) Control of local protein synthesis and initial events in myelination by action potentials. Science 333:1647–1651

    Article  PubMed  CAS  Google Scholar 

  • Wei Q, Miskimins WK, Miskimins R (2004) Sox10 acts as a tissue-specific transcription factor enhancing activation of the myelin basic protein gene promoter by p27Kip1 and Sp1. J Neurosci Res 78:796–802

    Article  PubMed  CAS  Google Scholar 

  • Wu MC, Lin X (2009) Prior biological knowledge-based approaches for the analysis of genome-wide expression profiles using gene sets and pathways. Stat Methods Med Res 18:577–593

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Dr. David C. Spray (Einstein) longtime collaboration on developing novel bioinformatics and comments on the biological interpretation of findings presented in this paper are gratefully acknowledged.

Author information

Authors and Affiliations

  1. D.P. Purpura Department of Neuroscience, Kennedy Center, Albert Einstein College of Medicine of Yeshiva University, Room 713, 1300 Morris Park Avenue, Bronx-New York, NY, 10461, USA

    Sanda Iacobas, Neil M. Thomas & Dumitru A. Iacobas

Authors
  1. Sanda Iacobas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neil M. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dumitru A. Iacobas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dumitru A. Iacobas.

Additional information

Communicated by S. Hohmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iacobas, S., Thomas, N.M. & Iacobas, D.A. Plasticity of the myelination genomic fabric. Mol Genet Genomics 287, 237–246 (2012). https://doi.org/10.1007/s00438-012-0673-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00438-012-0673-0

Keywords

Search

Navigation