Skip to main content
SpringerLink
Log in

ADNP/ADNP2 expression in oligodendrocytes: implication for myelin-related neurodevelopment

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Oligodendrocytes, the myelin-forming cells of the central nervous system, play important roles in brain development and maintenance. Activity-dependent neuroprotective protein (ADNP), an early marker essential for brain formation, interacts with microtubule end-binding proteins (EB1, EB2, and EB3). EB1 and EB3 are highly expressed in neurons (axons and dendritic spines, respectively) and EB1 enhancement of neurite outgrowth is attenuated by EB2. ADNP/EB presence in oligodendrocytes has not been studied so far. Here, we measured messenger RNA (mRNA) levels of ADNP and EB1–EB3 in rat brain oligodendrocytes during culture maturation and in rat brains during development (1, 35, and 75 days) in comparison with rat astrocytes, dorsal root ganglion (DRG) neurons, and the oligodendroglia cell lines (OLN-93 cell line, not expressing the microtubule-associated protein (MAP) tau, and OLN-93 cells stably transfected to express various forms of tau). Results showed that all transcripts studied were expressed in oligodendrocytes. ADNP and EB2 mRNA transcript content peaked at the time of oligodendrocyte maturation (5 days in vitro) and was highest in newborn rat brains compared with mature brains. ADNP2 (the only family member of ADNP), and EB1, although expressed in lower quantities, essentially paralleled ADNP and EB2 expression patterns, respectively. EB3 mRNA, peaking upon oligodendrocyte maturation, showed an apparent second peak of expression (10 days in vitro) and increased in the mature rat brain compared with the newborn brain. DRG cells expressed the highest levels of EB3, when compared with oligodendrocyte precursors and with astrocytes but not when compared with mature oligodendrocytes. Mature oligodendrocytes and oligodendrocyte precursors expressed ~30–40-fold more EB2 vs. EB3, and ~4–7-fold vs. ADNP. DRGs expressed ~5-fold more EB2 vs. EB3 and astrocytes showed an in-between (~20-fold) ratio. Only DRGs expressed similar EB1 and EB3 transcript levels, contrasting with oligodendrocyte and astrocytes (~10–30-fold more EB1). Astrocytes expressed more ADNP than DRGs and oligodendrocyte precursor cells (~2-fold) but not compared with mature oligodendrocytes. EB1 and EB3 were previously found to be associated with tau. Immortalized oligodendrocytes showed an intermediate phenotype of mRNA expression compared with oligodendrocyte precursor cells and mature oligodendrocytes with tau transfection reducing overall ADNP and EB expression. In summary, ADNPs and EBs are highly expressed in oligodendrocytes suggesting an impact on myelin formation in health and disease.

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
Fig. 3

Similar content being viewed by others

References

  • Arens J, Duong TT, Dehmelt L (2013) A morphometric screen identifies specific roles for microtubule-regulating genes in neuronal development of P19 stem cells. PLoS One 8:e79796

    Article  PubMed  PubMed Central  Google Scholar 

  • Bartzokis G, Lu PH, Geschwind DH, Tingus K, Huang D, Mendez MF, Edwards N, Mintz J (2007) Apolipoprotein E affects both myelin breakdown and cognition: implications for age-related trajectories of decline into dementia. Biol Psychiatry 62:1380–1387

    Article  CAS  PubMed  Google Scholar 

  • Bassan M, Zamostiano R, Davidson A, Pinhasov A, Giladi E, Perl O, Bassan H, Blat C, Gibney G, Glazner G, Brenneman DE, Gozes I (1999) Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem 72:1283–1293

    Article  CAS  PubMed  Google Scholar 

  • Bauer NG, Richter-Landsberg C (2006) The dynamic instability of microtubules is required for aggresome formation in oligodendroglial cells after proteolytic stress. J Mol Neurosci 29:153–168

  • Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927

    CAS  PubMed  Google Scholar 

  • Braitch M, Kawabe K, Nyirenda M, Gilles LJ, Robins RA, Gran B, Murphy S, Showe L, Constantinescu CS (2009) Expression of activity-dependent neuroprotective protein in the immune system: possible functions and relevance to multiple sclerosis. Neuroimmunomodulation 17:120–125

    Article  PubMed  PubMed Central  Google Scholar 

  • Chambers RA, Krystal JH, Self DW (2001) A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol Psychiatry 50:71–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Groot CO, Jelesarov I, Damberger FF, Bjelic S, Scharer MA, Bhavesh NS, Grigoriev I, Buey RM, Wuthrich K, Capitani G, Akhmanova A, Steinmetz MO (2010) Molecular insights into mammalian end-binding protein heterodimerization. J Biol Chem 285:5802–5814

    Article  PubMed  Google Scholar 

  • Dresner E, Agam G, Gozes I (2011) Activity-dependent neuroprotective protein (ADNP) expression level is correlated with the expression of the sister protein ADNP2: deregulation in schizophrenia. Eur Neuropsychopharmacol 21:355–361

    Article  CAS  PubMed  Google Scholar 

  • Dresner E, Malishkevich A, Arviv C, Leibman Barak S, Alon S, Ofir R, Gothilf Y, Gozes I (2012) Novel evolutionary-conserved role for the activity-dependent neuroprotective protein (ADNP) family that is important for erythropoiesis. J Biol Chem 287:40173–40185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med 354:942–955

    Article  CAS  PubMed  Google Scholar 

  • Furman S, Steingart RA, Mandel S, Hauser JM, Brenneman DE, Gozes I (2004) Subcellular localization and secretion of activity-dependent neuroprotective protein in astrocytes. Neuron Glia Biol 1:193–199

    Article  PubMed  PubMed Central  Google Scholar 

  • Gamsiz ED, Sciarra LN, Maguire AM, Pescosolido MF, van Dyck LI, Morrow EM (2015) Discovery of rare mutations in autism: elucidating neurodevelopmental mechanisms. Neurotherapeutics : J Am Soc Exp NeuroTherapeutics 12:553–571

    Article  CAS  Google Scholar 

  • Geraldo S, Khanzada UK, Parsons M, Chilton JK, Gordon-Weeks PR (2008) Targeting of the F-actin-binding protein drebrin by the microtubule plus-tip protein EB3 is required for neuritogenesis. Nat Cell Biol 10:1181–1189

    Article  CAS  PubMed  Google Scholar 

  • Goedert M, Crowther RA, Garner CC (1991) Molecular characterization of microtubule-associated proteins tau and MAP2. Trends Neurosci 14:193–199

    Article  CAS  PubMed  Google Scholar 

  • Goldbaum O, Oppermann M, Handschuh M, Dabir D, Zhang B, Forman MS, Trojanowski JQ, Lee VM, Richter-Landsberg C (2003) Proteasome inhibition stabilizes tau inclusions in oligodendroglial cells that occur after treatment with okadaic acid. J Neurosci 23:8872–8880

    CAS  PubMed  Google Scholar 

  • Goldbaum O, Richter-Landsberg C (2004) Proteolytic stress causes heat shock protein induction, tau ubiquitination, and the recruitment of ubiquitin to tau-positive aggregates in oligodendrocytes in culture. J Neurosci 24:5748–5757

  • Goldbaum O, Riedel M, Stahnke T, Richter-Landsberg C (2009) The small heat shock protein HSP25 protects astrocytes against stress induced by proteasomal inhibition. Glia 57:1566–1577

    Article  PubMed  Google Scholar 

  • Gorath M, Stahnke T, Mronga T, Goldbaum O, Richter-Landsberg C (2001) Developmental changes of tau protein and mRNA in cultured rat brain oligodendrocytes. Glia 36:89–101

    Article  CAS  PubMed  Google Scholar 

  • Gozes I (2015) The cytoskeleton as a drug target for neuroprotection: the case of the autism-mutated ADNP. Biological Chemistry

  • Gozes I, Richter-Landsberg C (1978) Identification of tubulin associated with rat brain myelin. FEBS Lett 95:169–172

    Article  CAS  PubMed  Google Scholar 

  • Gozes I, Helsmoortel C, Vandeweyer G, Van der Aa N, Kooy F, Sermone SB (2015) The compassionate side of neuroscience: Tony Sermone’s undiagnosed genetic journey-ADNP mutation. J Mol Neurosci

  • Gu C, Zhou W, Puthenveedu MA, Xu M, Jan YN, Jan LY (2006) The microtubule plus-end tracking protein EB1 is required for Kv1 voltage-gated K+ channel axonal targeting. Neuron 52:803–816

    Article  CAS  PubMed  Google Scholar 

  • Helsmoortel C, Vulto-van Silfhout AT, Coe BP, Vandeweyer G, Rooms L, van den Ende J, Schuurs-Hoeijmakers JH, Marcelis CL, Willemsen MH, Vissers LE, Yntema HG, Bakshi M, Wilson M, Witherspoon KT, Malmgren H, Nordgren A, Anneren G, Fichera M, Bosco P, Romano C, de Vries BB, Kleefstra T, Kooy RF, Eichler EE, Van der Aa N (2014) A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat Genet 46:380–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Honnappa S, Gouveia SM, Weisbrich A, Damberger FF, Bhavesh NS, Jawhari H, Grigoriev I, van Rijssel FJ, Buey RM, Lawera A, Jelesarov I, Winkler FK, Wuthrich K, Akhmanova A, Steinmetz MO (2009) An EB1-binding motif acts as a microtubule tip localization signal. Cell 138:366–376

    Article  CAS  PubMed  Google Scholar 

  • Jaworski J, Kapitein LC, Gouveia SM, Dortland BR, Wulf PS, Grigoriev I, Camera P, Spangler SA, Di Stefano P, Demmers J, Krugers H, Defilippi P, Akhmanova A, Hoogenraad CC (2009) Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity. Neuron 61:85–100

    Article  CAS  PubMed  Google Scholar 

  • Kalbfuss B, Mabon SA, Misteli T (2001) Correction of alternative splicing of tau in frontotemporal dementia and parkinsonism linked to chromosome 17. J Biol Chem 276:42986–42993

    Article  CAS  PubMed  Google Scholar 

  • Komarova Y, Lansbergen G, Galjart N, Grosveld F, Borisy GG, Akhmanova A (2005) EB1 and EB3 control CLIP dissociation from the ends of growing microtubules. Mol Biol Cell 16:5334–5345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kushnir M, Dresner E, Mandel S, Gozes I (2008) Silencing of the ADNP-family member, ADNP2, results in changes in cellular viability under oxidative stress. J Neurochem 105:537–545

    Article  CAS  PubMed  Google Scholar 

  • Magen I, Gozes I (2013) Microtubule-stabilizing peptides and small molecules protecting axonal transport and brain function: focus on davunetide (NAP). Neuropeptides 47:489–495

    Article  CAS  PubMed  Google Scholar 

  • Magen I, Gozes I (2014) Davunetide: peptide therapeutic in neurological disorders. Curr Med Chem

  • Malishkevich A, Amram N, Hacohen-Kleiman G, Magen I, Giladi E, Gozes I (2015) Activity-dependent neuroprotective protein (ADNP) exhibits striking sexual dichotomy impacting on autistic and Alzheimer’s pathologies. Transl Psychiatry 5:e501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mandel S, Gozes I (2007) Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex. J Biol Chem 282:34448–34456

    Article  CAS  PubMed  Google Scholar 

  • Mandel S, Rechavi G, Gozes I (2007) Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate genes essential for embryogenesis. Dev Biol 303:814–824

    Article  CAS  PubMed  Google Scholar 

  • Mandel S, Spivak-Pohis I, Gozes I (2008) ADNP differential nucleus/cytoplasm localization in neurons suggests multiple roles in neuronal differentiation and maintenance. J Mol Neurosci 35:127–141

    Article  CAS  PubMed  Google Scholar 

  • Merenlender-Wagner A, Shemer Z, Touloumi O, Lagoudaki R, Giladi E, Andrieux A, Grigoriadis NC, Gozes I (2014) New horizons in schizophrenia treatment: autophagy protection is coupled with behavioral improvements in a mouse model of schizophrenia. Autophagy 0

  • Merenlender-Wagner A, Malishkevich A, Shemer Z, Udawela M, Gibbons A, Scarr E, Dean B, Levine J, Agam G, Gozes I (2015) Autophagy has a key role in the pathophysiology of schizophrenia. Mol Psychiatry 20:126–132

    Article  CAS  PubMed  Google Scholar 

  • Muller R, Heinrich M, Heck S, Blohm D, Richter-Landsberg C (1997) Expression of microtubule-associated proteins MAP2 and tau in cultured rat brain oligodendrocytes. Cell Tissue Res 288:239–249

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa H, Koyama K, Murata Y, Morito M, Akiyama T, Nakamura Y (2000) EB3, a novel member of the EB1 family preferentially expressed in the central nervous system, binds to a CNS-specific APC homologue. Oncogene 19:210–216

    Article  CAS  PubMed  Google Scholar 

  • Noack M, Leyk J, Richter-Landsberg C (2014) HDAC6 inhibition results in tau acetylation and modulates tau phosphorylation and degradation in oligodendrocytes. Glia 62:535–547

    Article  PubMed  Google Scholar 

  • Noll E, Miller RH (1993) Oligodendrocyte precursors originate at the ventral ventricular zone dorsal to the ventral midline region in the embryonic rat spinal cord. Development 118:563–573

    CAS  PubMed  Google Scholar 

  • Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL (2008) The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet 9:516–526

    Article  CAS  PubMed  Google Scholar 

  • Ou-Yang MH, Xu F, Liao MC, Davis J, Robinson JK, Van Nostrand WE (2015) The N-terminal region of myelin basic protein reduces fibrillar amyloid-beta deposition in Tg-5xFAD mice. Neurobiol Aging 36:801–811

    Article  CAS  PubMed  Google Scholar 

  • Oz S, Kapitansky O, Ivashco-Pachima Y, Malishkevich A, Giladi E, Skalka N, Rosin-Arbesfeld R, Mittelman L, Segev O, Hirsch JA, Gozes I (2014) The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins. Mol Psychiatry 19:1115–1124

    Article  CAS  PubMed  Google Scholar 

  • Pescosolido MF, Schwede M, Johnson Harrison A, Schmidt M, Gamsiz ED, Chen WS, Donahue JP, Shur N, Jerskey BA, Phornphutkul C, Morrow EM (2014) Expansion of the clinical phenotype associated with mutations in activity-dependent neuroprotective protein. J Med Genet 51:587–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pinhasov A, Mandel S, Torchinsky A, Giladi E, Pittel Z, Goldsweig AM, Servoss SJ, Brenneman DE, Gozes I (2003) Activity-dependent neuroprotective protein: a novel gene essential for brain formation. Brain Res Dev Brain Res 144:83–90

    Article  CAS  PubMed  Google Scholar 

  • Quintana FJ, Zaltzman R, Fernandez-Montesinos R, Herrera JL, Gozes I, Cohen IR, Pozo D (2006) NAP, a peptide derived from the activity-dependent neuroprotective protein, modulates macrophage function. Ann N Y Acad Sci 1070:500–506

    Article  CAS  PubMed  Google Scholar 

  • Rajendran L, Bali J, Barr MM, Court FA, Kramer-Albers EM, Picou F, Raposo G, van der Vos KE, van Niel G, Wang J, Breakefield XO (2014) Emerging roles of extracellular vesicles in the nervous system. J Neurosci 34:15482–15489

    Article  PubMed  PubMed Central  Google Scholar 

  • Richter-Landsberg C, Gorath M (1999) Developmental regulation of alternatively spliced isoforms of mRNA encoding MAP2 and tau in rat brain oligodendrocytes during culture maturation. J Neurosci Res 56:259–270

    Article  CAS  PubMed  Google Scholar 

  • Richter-Landsberg C, Heinrich M (1996) OLN-93: a new permanent oligodendroglia cell line derived from primary rat brain glial cultures. J Neurosci Res 45:161–173

    Article  CAS  PubMed  Google Scholar 

  • Richter-Landsberg C, Leyk J (2013) Inclusion body formation, macroautophagy, and the role of HDAC6 in neurodegeneration. Acta Neuropathol 126:793–807

    Article  CAS  PubMed  Google Scholar 

  • Sayas CL, Tortosa E, Bollati F, Ramirez-Rios S, Arnal I, Avila J (2015) Tau regulates the localization and function of End-binding proteins 1 and 3 in developing neuronal cells. J Neurochem 133:653–667

    Article  CAS  PubMed  Google Scholar 

  • Schirer Y, Malishkevich A, Ophir Y, Lewis J, Giladi E, Gozes I (2014) Novel marker for the onset of frontotemporal dementia: early increase in activity-dependent neuroprotective protein (ADNP) in the face of Tau mutation. PLoS One 9:e87383

    Article  PubMed  PubMed Central  Google Scholar 

  • Schmitt A, Steyskal C, Bernstein HG, Schneider-Axmann T, Parlapani E, Schaeffer EL, Gattaz WF, Bogerts B, Schmitz C, Falkai P (2009) Stereologic investigation of the posterior part of the hippocampus in schizophrenia. Acta Neuropathol 117:395–407

    Article  PubMed  Google Scholar 

  • Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108

    Article  CAS  PubMed  Google Scholar 

  • Seiberlich V, Bauer NG, Schwarz L, Ffrench-Constant C, Goldbaum O, Richter-Landsberg C (2015) Downregulation of the microtubule associated protein Tau impairs process outgrowth and myelin basic protein mRNA transport in oligodendrocytes. Glia

  • Sen I, Veprintsev D, Akhmanova A, Steinmetz MO (2013) End binding proteins are obligatory dimers. PLoS One 8:e74448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sokolowska P, Passemard S, Mok A, Schwendimann L, Gozes I, Gressens P (2011) Neuroprotective effects of NAP against excitotoxic brain damage in the newborn mice: implications for cerebral palsy. Neuroscience 173:156–168

    Article  CAS  PubMed  Google Scholar 

  • Stepanova T, Slemmer J, Hoogenraad CC, Lansbergen G, Dortland B, De Zeeuw CI, Grosveld F, van Cappellen G, Akhmanova A, Galjart N (2003) Visualization of microtubule growth in cultured neurons via the use of EB3-GFP (end-binding protein 3-green fluorescent protein). J Neurosci 23:2655–2664

    CAS  PubMed  Google Scholar 

  • Su LK, Qi Y (2001) Characterization of human MAPRE genes and their proteins. Genomics 71:142–149

    Article  CAS  PubMed  Google Scholar 

  • Vulih-Shultzman I, Pinhasov A, Mandel S, Grigoriadis N, Touloumi O, Pittel Z, Gozes I (2007) Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model. J Pharmacol Exp Ther 323:438–449

    Article  CAS  PubMed  Google Scholar 

  • Zamostiano R, Pinhasov A, Gelber E, Steingart RA, Seroussi E, Giladi E, Bassan M, Wollman Y, Eyre HJ, Mulley JC, Brenneman DE, Gozes I (2001) Cloning and characterization of the human activity-dependent neuroprotective protein. J Biol Chem 276:708–714

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Support was provided by the AMN Foundation, Israel Science Foundation and the Israeli Ministry for Science Technology and Space. Professor Illana Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, the Director of the Levie-Edersheim-Gitter Institute for Functional Brain Imaging, and the Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology at Tel Aviv University and a Humboldt Award Recipient, currently a fellow at Hanse-Wissenschaftskolleg (HWK), Germany. This study is in partial fulfillment for the Ph.D. requirement for Mrs. Anna Malishkevich at the Dr. Miriam and Sheldon G. Adelson Graduate School in Medicine.

Author information

Authors and Affiliations

  1. The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Dr. Diana and Zelman Elton (Elbaum) Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, The Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 69978, Israel

    Anna Malishkevich & Illana Gozes

  2. Department of Neuroscience, Molecular Neurobiology, and Research Center Neurosensory Science, University of Oldenburg, 26111, Oldenburg, Germany

    Janina Leyk, Olaf Goldbaum & Christiane Richter-Landsberg

Authors
  1. Anna Malishkevich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Janina Leyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olaf Goldbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christiane Richter-Landsberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Illana Gozes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Illana Gozes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Malishkevich, A., Leyk, J., Goldbaum, O. et al. ADNP/ADNP2 expression in oligodendrocytes: implication for myelin-related neurodevelopment. J Mol Neurosci 57, 304–313 (2015). https://doi.org/10.1007/s12031-015-0640-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-015-0640-4

Keywords

Search

Navigation