Skip to main content
Log in

Glu-tubulin is a marker for Schwann cells and can distinguish between schwannomas and neurofibromas

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Schwann cells generate myelin sheaths around the axons of the peripheral nervous system, thus facilitating efficient nerve impulse propagation. Two main tumor types can arise from peripheral nerves, schwannomas and neurofibromas, which are sometimes difficult to distinguish and may require the use of diagnostic biomarkers. Here, we characterize a new marker for Schwann cells and its potential use as a diagnostic marker for schwannomas. Immunohistochemistry for Glu-tubulin, a posttranslational modification of α-tubulin, was performed in mouse and human tissues. This technique labels Schwann cells but not oligodendrocytes. All peripheral nerves were immunoreactive for this antibody, including large nerve trunks, thin myelinated nerves, as well as the myenteric and submucous plexus of the digestive tract. In the mouse brain, many neurons were immunoreactive for Glu-tubulin but oligodendrocytes were negative. During embryo development, immunoreactive nerves were already found at E10. In Schwann cells, the staining is restricted to the myelin sheaths and is not present in the perinuclear cytoplasm or the Ranvier nodes. Primary cultures of fibroblasts and Schwann cells were established from mouse sciatic nerves, and Western blot analysis showed that Glu-tubulin immunoreactivity was found in the Schwann cells but not in the fibroblasts. Clinical specimens of schwannomas (n = 20) and neurofibromas (n = 20) were stained with anti-Glu-tubulin antibodies. Schwannomas presented a strong staining in all tumor cells, whereas neurofibromas had a light speckled staining pattern, easily distinguishable from the one found in schwannomas. In conclusion, Glu-tubulin can be used as a marker of Schwann cells and can help in diagnosing peripheral nerve tumors.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Al-Jallad HF, Myneni VD, Piercy-Kotb SA, Chabot N, Mulani A, Keillor JW, Kaartinen MT (2011) Plasma membrane factor XIIIA transglutaminase activity regulates osteoblast matrix secretion and deposition by affecting microtubule dynamics. PLoS One 6:e15893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baraban M, Mensch S, Lyons DA (2016) Adaptive myelination from fish to man. Brain Res. doi:10.1016/j.brainres.2015.10.026

  • Boggs JM, Homchaudhuri L, Ranagaraj G, Liu Y, Smith GS, Harauz G (2014) Interaction of myelin basic protein with cytoskeletal and signaling proteins in cultured primary oligodendrocytes and N19 oligodendroglial cells. BMC Res Notes 7:387

    Article  PubMed  PubMed Central  Google Scholar 

  • Fernandez AP, Serrano J, Tessarollo L, Cuttitta F, Martinez A (2008) Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions. Proc Natl Acad Sci USA 105:12581–12586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fine SW, McClain SA, Li M (2004) Immunohistochemical staining for calretinin is useful for differentiating schwannomas from neurofibromas. Am J Clin Pathol 122:552–559

    Article  PubMed  Google Scholar 

  • Friedrich RE, Behrendt CA, Glatzel M, Hagel C (2015) Vascular innervation in benign neurofibromas of patients with neurofibromatosis type 1. Anticancer Res 35:6509–6516

    CAS  PubMed  Google Scholar 

  • Garcia-Sanmartin J, Larrayoz IM, Martinez A (2016) Adrenomedullin regulates club cell recovery following lung epithelial injury. Histol Histopathol 31:663–673

    PubMed  Google Scholar 

  • Garnham CP, Roll-Mecak A (2012) The chemical complexity of cellular microtubules: tubulin post-translational modification enzymes and their roles in tuning microtubule functions. Cytoskeleton (Hoboken) 69:442–463

    Article  CAS  Google Scholar 

  • Godinho MJ, Teh L, Pollett MA, Goodman D, Hodgetts SI, Sweetman I, Walters M, Verhaagen J, Plant GW, Harvey AR (2013) Immunohistochemical, ultrastructural and functional analysis of axonal regeneration through peripheral nerve grafts containing Schwann cells expressing BDNF, CNTF or NT3. PLoS One 8:e69987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gray MH, Smoller BR, McNutt NS, Hsu A (1990) Immunohistochemical demonstration of factor XIIIa expression in neurofibromas. A practical means of differentiating these tumors from neurotized melanocytic nevi and schwannomas. Arch Dermatol 126:472–476

    Article  CAS  PubMed  Google Scholar 

  • Han H, Myllykoski M, Ruskamo S, Wang C, Kursula P (2013) Myelin-specific proteins: a structurally diverse group of membrane-interacting molecules. BioFactors 39:233–241

    Article  CAS  PubMed  Google Scholar 

  • Hirose T, Tani T, Shimada T, Ishizawa K, Shimada S, Sano T (2003) Immunohistochemical demonstration of EMA/Glut1-positive perineurial cells and CD34-positive fibroblastic cells in peripheral nerve sheath tumors. Mod Pathol 16:293–298

    Article  PubMed  Google Scholar 

  • Jensen SM, Gazdar AF, Cuttitta F, Russell EK, Linnoila RI (1990) A comparison of synaptophysin, chromogranin, and L-dopa decarboxylase as markers for neuroendocrine differentiation in lung cancer cell lines. Cancer Res 50:6068–6074

    CAS  PubMed  Google Scholar 

  • Jessen KR, Mirsky R, Lloyd AC (2015) Schwann cells: development and role in nerve repair. Cold Spring Harb Perspect Biol 7:a020487

    Article  PubMed  Google Scholar 

  • King R (2013) Microscopic anatomy: normal structure. Handb Clin Neurol 115:7–27

    Article  PubMed  Google Scholar 

  • Kostic M, Stojanovic I, Marjanovic G, Zivkovic N, Cvetanovic A (2015) Deleterious versus protective autoimmunity in multiple sclerosis. Cell Immunol 296:122–132

    Article  CAS  PubMed  Google Scholar 

  • Lehmann HC, Hoke A (2016) Use of engineered Schwann cells in peripheral neuropathy: hopes and hazards. Brain Res. doi:10.1016/j.brainres.2015.10.040

  • Martinez A, Pio R, Lopez J, Cuttitta F (2001) Expression of the adrenomedullin binding protein, complement factor H, in the pancreas and its physiological impact on insulin secretion. J Endocrinol 170:503–511

    Article  CAS  PubMed  Google Scholar 

  • Mobius W, Patzig J, Nave KA, Werner HB (2008) Phylogeny of proteolipid proteins: divergence, constraints, and the evolution of novel functions in myelination and neuroprotection. Neuron Glia Biol 4:111–127

    Article  PubMed  Google Scholar 

  • Nascimento AF, Fletcher CD (2007) The controversial nosology of benign nerve sheath tumors: neurofilament protein staining demonstrates intratumoral axons in many sporadic schwannomas. Am J Surg Pathol 31:1363–1370

    Article  PubMed  Google Scholar 

  • Rostovtseva TK, Gurnev PA, Chen MY, Bezrukov SM (2012) Membrane lipid composition regulates tubulin interaction with mitochondrial voltage-dependent anion channel. J Biol Chem 287:29589–29598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salzer JL (2015) Schwann cell myelination. Cold Spring Harb Perspect Biol 7:a020529

    Article  PubMed  Google Scholar 

  • Sedzik J, Jastrzebski JP, Grandis M (2015) Glycans of myelin proteins. J Neurosci Res 93:1–18

    Article  CAS  PubMed  Google Scholar 

  • Steinman L (2015) No quiet surrender: molecular guardians in multiple sclerosis brain. J Clin Invest 125:1371–1378

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang S, Cui C, Hitomi K, Kaartinen MT (2014) Detyrosinated Glu-tubulin is a substrate for cellular factor XIIIA transglutaminase in differentiating osteoblasts. Amino Acids 46:1513–1526

    Article  CAS  PubMed  Google Scholar 

  • Whipple RA, Cheung AM, Martin SS (2007) Detyrosinated microtubule protrusions in suspended mammary epithelial cells promote reattachment. Exp Cell Res 313:1326–1336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Whipple RA, Matrone MA, Cho EH, Balzer EM, Vitolo MI, Yoon JR, Ioffe OB, Tuttle KC, Yang J, Martin SS (2010) Epithelial-to-mesenchymal transition promotes tubulin detyrosination and microtentacles that enhance endothelial engagement. Cancer Res 70:8127–8137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodhoo A, Alonso MB, Droggiti A, Turmaine M, D’Antonio M, Parkinson DB, Wilton DK, Al-Shawi R, Simons P, Shen J, Guillemot F, Radtke F, Meijer D, Feltri ML, Wrabetz L, Mirsky R, Jessen KR (2009) Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat Neurosci 12:839–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin X, Kiryu-Seo S, Kidd GJ, Feltri ML, Wrabetz L, Trapp BD (2015) Proteolipid protein cannot replace P0 protein as the major structural protein of peripheral nervous system myelin. Glia 63:66–77

    Article  PubMed  Google Scholar 

  • Yu I, Garnham CP, Roll-Mecak A (2015) Writing and reading the tubulin code. J Biol Chem 290:17163–17172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng L, Wu X, Kreis ME, Yu Z, Feng L, Chen C, Xu B, Bu Z, Li Z, Ji J (2014) Clinicopathological and immunohistochemical characterisation of gastric schwannomas in 29 cases. Gastroenterol Res Pract 2014:202960

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge Ms. Judit Narro for excellent technical work.

Funding

This study was funded by Fundación Rioja Salud.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alfredo Martínez.

Ethics declarations

Conflict of interest

The authors have nothing to disclose.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

García-Sanmartín, J., Rubio-Mediavilla, S., Sola-Gallego, J.J. et al. Glu-tubulin is a marker for Schwann cells and can distinguish between schwannomas and neurofibromas. Histochem Cell Biol 146, 467–477 (2016). https://doi.org/10.1007/s00418-016-1455-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-016-1455-2

Keywords

Navigation