Neuroscience and Behavioral Physiology

, Volume 42, Issue 3, pp 215–222 | Cite as

Microtubule-Associated Proteins as Indicators of Differentiation and the Functional State of Nerve Cells

  • D. E. Korzhevskii
  • M. N. Karpenko
  • O. V. Kirik

This review addresses the characteristics of the proteins beta-tubulin III, MAP2, and doublecortin, which are involved in the organization, stabilization, and functioning of nerve cell cytoskeletal microtubules. Because of their structural-functional properties, these proteins can be regarded as neurogenesis-associated differentiation markers and as indicators of the functional state of nerve cells in normal conditions and pathology. Published reports show that these proteins have important structural and transport functions in nerve cells and are required for neuron-specific intracellular processes. However, existing knowledge of the functional role of these proteins in nerve cells is inadequate and requires significant widening, without which experimental results cannot be interpreted unambiguously.


nerve cells microtubules doublecortin tubulin 


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  1. 1.
    O. S. Alekseeva, D. E. Korzhevskii, I. P. Grigoriev, et al., “Preadaptation of nitrogen anesthesia and impairment of brain structure in rats during hypoxia,” Zh. Evolyuts. Biokhim., 46, No. 4, 311–315 (2010).Google Scholar
  2. 2.
    B. I. Berdiev, R. A. Poltavtseva, O. V. Podgornyi, et al., “Molecular genetic and immunotype analysis of transcription factor Pax6 and neuronal differentiation markers in the neocortex and retina of human fetuses in vivo and in vitro,” Kletochn. Tekhnol. Biol. Med., No. 4, 206–213 (2009).Google Scholar
  3. 3.
    A. V. Gilyarov, “Nestin in central nervous system cells,” Morfologiya, 131, No. 1, 85–90 (2007).Google Scholar
  4. 4.
    D. E. Korzhevskii, E. G. Gilerovich, N. N. Zinkova, et al., “Immunochemical detection of brain neurons using the selective marker NeuN,” Morfologiya, 128, No. 5, 76–78 (2005).Google Scholar
  5. 5.
    D. E. Korzhevskii and A. V. Gilyarov, “Immunocytochemical detection of tissue antigens after prolonged storage of specimens in methylsalicylate,” Morfologiya, 134, No. 6, 76–78 (2008).Google Scholar
  6. 6.
    D. E. Korzhevskii, E. S. Petrova, O. V. Kirik, et al., “Neural markers used in studies of stem cell differentiation,” Kletochn. Transplant. Tkan. Inzhen., 5, No. 3, 1–7 (2010).Google Scholar
  7. 7.
    D. E. Korzhevskii, E. S. Petrova, O. V. Kirik, and V. A. Otellin, “Assessment of neuron differentiation in rat embryogenesis using immunocytochemical detection of doublecortin,” Morfologiya, 133, No. 4, 7–10 (2008).Google Scholar
  8. 8.
    D. E. Korzhevskii, L. I. Khozhai, E. G. Gilerovich, et al., “Current morphological methods for assessing destructive processes developing in the brain in response to harmful influences,” in: Structural-Functional and Neurochemical Patterns of Asymmetry in Brain Plasticity [in Russian], IZPTs Informkniga, Moscow (2006), pp. 139–142.Google Scholar
  9. 9.
    A. A. Sosunov and Yu. A. Chelyshev, “Neural stem cells in the brain,” Usp. Fiziol. Nauk., 33, No. 1, 17–28 (2002).PubMedGoogle Scholar
  10. 10.
    J. S. Albala,Y. Kress,W. K. Liu, et al., “Human microtubule-associated protein-2c localizes to dendrites and axons in fetal spinal motoneurons,” J. Neurochem., 64, No. 6, 2480–2490 (1995).PubMedCrossRefGoogle Scholar
  11. 11.
    A. Alexa, P. Tompa, A. Baki, et al., “Mutual protection of microtubule-associated protein 2 (MAP2) and cyclic AMP-dependent protein kinase II against mu-calpain,” J. Neurosci. Res., 44, No. 5, 438–445 (1996).PubMedCrossRefGoogle Scholar
  12. 12.
    J. E. Alexander, D. F. Hunt, M. K. Lee, et al., “Characterization of post-translational modifications in neuron-specific class III betatubulin by mass spectrometry,” Proc. Natl. Acad. Sci. USA, 88, No. 11, 4685–4689 (1991).PubMedCrossRefGoogle Scholar
  13. 13.
    O. Avwenagha, G. Campbell, and M. M. Bird, “Distribution of GAP-43, beta-III tubulin and F-actin in developing and regenerating axons and their growth cones in vitro, following neurotrophin treatment,” J. Neurocytol., 32, No. 9, 1077–1089 (2003).PubMedCrossRefGoogle Scholar
  14. 14.
    J. Bai, R. L. Ramos, and J. B. Ackman, “RNAi reveals doublecortin is required for radial migration in rat neocortex,” Nat. Neurosci., 6, No. 12, 1277–1283 (2003).PubMedCrossRefGoogle Scholar
  15. 15.
    A. Banerjee, M. C. Roach, P. Trcka, and R. F. Ludueña, “Increased microtubule assembly in bovine brain tubulin lacking the type III isotype of beta-tubulin,” J. Biol. Chem., 265, No. 3, 1794–1799 (1990).PubMedGoogle Scholar
  16. 16.
    L. I. Binder, A. Frankfurter, H. Kim, et al., “Heterogeneity of microtubule-associated protein 2 during rat brain development,” Proc. Natl. Acad. Sci. USA, 81, No. 17, 5613–5617 (1984).PubMedCrossRefGoogle Scholar
  17. 17.
    I. Bystron, P. Rakic, Z. Molnar, and C. Blakemore, “The first neurons of the human cerebral cortex,” Nat. Neurosci., 9, No. 7, 880–886 (2006).PubMedCrossRefGoogle Scholar
  18. 18.
    C. C. Cunningham, N. Leclerc, L. A. Flanagan, et al., “Microtubuleassociated protein 2c reorganizes both microtubules and microfilaments into distinct cytological structures in an actin-binding protein-280-deficient melanoma cell line,” J. Cell Biol., 136, No. 4, 845–857 (1997).PubMedCrossRefGoogle Scholar
  19. 19.
    M. C. Daou, T. W. Smith, N. S. Litofsky, et al., “Doublecortin is preferentially expressed in invasive human brain tumors,” Acta Neuropathol., 110, No. 5, 472–480 (2005).PubMedCrossRefGoogle Scholar
  20. 20.
    M. C. De Wit, M. H. Lequin, I. F. de Coo, et al., “Cortical brain malformations: effect of clinical, neuroradiological, and modern genetic classification,” Arch. Neurol., 65, No. 3, 358–366 (2008).PubMedCrossRefGoogle Scholar
  21. 21.
    L. Dehmelt and S. Halpain, “Actin and microtubules in neurite initiation: are MAPs the missing link?” J. Neurobiol., 58, No. 1, 18–33 (2004).PubMedCrossRefGoogle Scholar
  22. 22.
    A. Dellarole and M. Grilli, “Adult dorsal root ganglia sensory neurons express the early neuronal fate marker doublecortin,” J. Comp. Neurol., 511, No. 3, 318–328 (2008).PubMedCrossRefGoogle Scholar
  23. 23.
    K. Dennis, M. Uittenbogaard, A. Chiaramello, and S. A. Moody, “Cloning and characterization of the 5’-flanking region of the rat neuron-specific Class III beta-tubulin gene,” Gene, 294, No. 1–2, 269–277 (2002).PubMedCrossRefGoogle Scholar
  24. 24.
    V. Des Portes, J. M. Pinard, P. Billuart, et al., “A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome,” Cell, 92, No. 1, 51–61 (1998).PubMedCrossRefGoogle Scholar
  25. 25.
    T. A. Deuel, J. S. Liu, and J. C. Corbo, “Genetic interaction between doublecortin and doublecortin-like kinase in neuronal migration and axon outgrowth,” Neuron, 49, No. 1, 41–53 (2006).PubMedCrossRefGoogle Scholar
  26. 26.
    J. H. Dinsmore and F. Solomon, “Inhibition of MAP2 expression affects both morphological and cell division phenotypes of neuronal differentiation,” Cell, 64, No. 4, 817–826 (1991).PubMedCrossRefGoogle Scholar
  27. 27.
    E. Dráberová, L. Del Valle, J. Gordon, et al., “Class III beta-tubulin is constitutively coexpressed with glial fibrillary acidic protein and nestin in midgestational human fetal astrocytes: implications for phenotypic identity,” J. Neuropathol. Exp. Neurol., 67, No. 4, 341–354 (2008).PubMedCrossRefGoogle Scholar
  28. 28.
    M. L. Fanarraga, J. Avila, and J. C. Zabala, “Expression of unphosphorylated class III beta-tubulin isotype in neuroepithelial cells demonstrates neuroblast commitment and differentiation,” Eur. J. Neurosci., 11, No. 2, 516–527 (1999).PubMedCrossRefGoogle Scholar
  29. 29.
    C. A. Farah and N. Leclerc, “HMWMAP2: new perspectives on a pathway to dendritic identity,” Cell Motil. Cytoskeleton, 65, No. 7, 515–527 (2008).PubMedCrossRefGoogle Scholar
  30. 30.
    C. A. Farah, D. Liazoghli, S. Perrault, et al., “Interaction of microtubule-associated protein-2 and p63: a new link between microtubules and rough endoplasmic reticulum membranes in neurons,” J. Biol. Chem., 280, No. 10, 9439–9449 (2005).PubMedCrossRefGoogle Scholar
  31. 31.
    H. Felgner, R. Frank, J. Biernat, et al., “Domains of neuronal microtubule-associated proteins and flexural rigidity of microtubules,” J. Cell Biol., 138, No. 5, 1067–1075 (1997).PubMedCrossRefGoogle Scholar
  32. 32.
    L. Ferhat, A. Represa,W. Ferhat, et al., “MAP2d mRNA is expressed in identified neuronal populations in the developing and adult rat brain and its subcellular distribution differs from that of MAP2b in hippocampal neurones,” Eur. J. Neurosci., 10, No. 1, 161–171 (1988).CrossRefGoogle Scholar
  33. 33.
    M. M. Folkerts, R. F. Berman, J. P. Muizelaar, and J. A. Rafols, “Disruptions of MAP-2 immunostaining in rat hippocampus after traumatic brain injury,” J. Neurotrauma, 15, No. 2, 349–363 (1998).PubMedCrossRefGoogle Scholar
  34. 34.
    G. Friocourt, A. Koulakoff, P. Chafey, et al., “Doublecortin functions at the extremities of growing neuronal processes,” Cereb. Cortex, 13, No. 6, 620–626 (2003).PubMedCrossRefGoogle Scholar
  35. 35.
    G. Friocourt, J. S. Liu, M. Antypa, et al., “Both doublecortin and doublecortin-like kinase play a role in cortical interneuron migration,” J. Neurosci., 27, No. 14, 3875–3883 (2007).PubMedCrossRefGoogle Scholar
  36. 36.
    O. Gonzalez-Perez and A. Quinones-Hinojosa, “Dose-dependent effect of EGF on migration and differentiation of adult subventricular zone astrocytes,” Glia, 58, No. 8, 975–983 (2010).PubMedGoogle Scholar
  37. 37.
    M. E. Graham, P. Ruma-Haynes, A. G. Capes-Davis, et al., “Multisite phosphorylation of doublecortin by cyclin-dependent kinase 5,” Biochem. J., 381, No. 2, 471–481 (2004).PubMedCrossRefGoogle Scholar
  38. 38.
    J. Guo, C. Walss-Bass, and R. F. Ludueña, “The beta isotypes of tubulin in neuronal differentiation,” Cytoskeleton (Hoboken), 67, No. 7, 431–441 (2010).Google Scholar
  39. 39.
    J. W. Hammond, D. Cai, and K. J. Verhey, “Tubulin modifications and their cellular functions,” Curr. Opin. Cell Biol., 20, No. 1, 71–78 (2008).PubMedCrossRefGoogle Scholar
  40. 40.
    A. Harada, J. Teng, Y. Takei, et al., “MAP2 is required for dendrite elongation, PKA anchoring in dendrites, and proper PKA signal transduction,” J. Cell Biol., 158, No. 3, 541–549 (2002).PubMedCrossRefGoogle Scholar
  41. 41.
    J. W. Huw, R. Raghupathi, H. L. Laurer, et al., “Transient loss of microtubule-associated protein 2 immunoreactivity after moderate brain injury in mice,” J. Neurotrauma, 20, No. 10, 975–984 (2003).CrossRefGoogle Scholar
  42. 42.
    Y. Q. Jiang and M. M. Oblinger, “Differential regulation of beta III and other tubulin genes during peripheral and central neuron development,” J. Cell Sci., 103, No. 3, 643–651 (1992).PubMedGoogle Scholar
  43. 43.
    N. Kalcheva, J. M. Rockwood,Y. Kress, et al., “Molecular and functional characteristics of MAP-2a versus MAP-2b to induce stable microtubules in COS cells,” Cell Motil. Cytoskeleton, 40, No. 3, 272–285 (1998).PubMedCrossRefGoogle Scholar
  44. 44.
    C. Kappeler,Y. Saillour, J. B. Baudoin, et al., “Branching and neucleokinesis defects in migrating interneurons derived from doublecortin knockout mice,” Hum. Mol. Genet., 15, No. 9, 1387–1400 (2006).PubMedCrossRefGoogle Scholar
  45. 45.
    G. Kerjan, H. Koizumi, E. B. Han, et al., “Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures,” Proc. Natl. Acad. Sci. USA, 106, No. 16, 6766–6771 (2009).PubMedCrossRefGoogle Scholar
  46. 46.
    I. A. Khan and R. F. Ludueña, “Phosphorylation of beta III-tubulin,” Biochemistry, 35, No. 12, 3704–3711 (1996).PubMedCrossRefGoogle Scholar
  47. 47.
    M. H. Kim, T. Cierpicki, U. Derewenda, et al., “The DCX-domain tandems of doublecortin and doublecortin-like kinase,” Nat. Struct. Biol., 10, No. 5, 324–333 (2003).PubMedCrossRefGoogle Scholar
  48. 48.
    H. Koizumi, T. Tanaka, and J. G. Gleeson, “Doublecortin-like kinase functions with doublecortin to mediate fiber tract decussation and neuronal migration,” Neuron, 49, No. 1, 55–66 (2006).PubMedCrossRefGoogle Scholar
  49. 49.
    D. Kozireski-Chuback, G. Wu, and R. W. Ledeen, “Upregulation of nuclear GM1 accompanies axon-like, but not dendrite-like, outgrowth in NG108-15 cells,” J. Neurosci. Res., 55, No. 1, 107–118 (1999).PubMedCrossRefGoogle Scholar
  50. 50.
    S. L. Kewi, A. Clement, A. Faissner, and R. Brandt, “Differential interactions of MAP2, tau and MAP5 during axogenesis in culture,” Neuroreport, 9, No. 6, 1035–1040 (1998).CrossRefGoogle Scholar
  51. 51.
    K. Langnaese, C. Seidenbecher, H. Wex, et al., “protein components of a rat brain synaptic junctional protein preparation,” Brain Res. Mol. Brain Res., 42, No. 1, 118–122 (1996).PubMedCrossRefGoogle Scholar
  52. 52.
    L. Kiu, E. E. Geisert, A. Frankfurter, et al., “A transgenic mouse class-III beta tubulin reporter using yellow fluorescent protein,” Genesis, 45, No. 9, 560–569 (2007).CrossRefGoogle Scholar
  53. 53.
    L. A. Lopez and M. P. Sheetz, “Steric inhibition of cytoplasmic dynein and kinesin motility by MAP2,” Cell Motil. Cytoskeleton, 24, No. 1, 1–16 (1993).PubMedCrossRefGoogle Scholar
  54. 54.
    K. L. Loveland, T. M. Hayes, A. Meinhardt, et al., “Microtubuleassociated protein-2 in the rat testis: a novel site of expression,” Biol. Reprod., 54, No. 4, 896–904 (1996).PubMedCrossRefGoogle Scholar
  55. 55.
    R. F. Ludeña, “Multiple forms of tubulin: different gene products and covalent modifications,” Int. Rev. Cytol., 178, 207–275 (1998).CrossRefGoogle Scholar
  56. 56.
    W. Matsunaga, S. Miyata, and T. Kiyohara, “Redistribution of MAP2 immunoreactivity in the neurohypophyseal astrocytes of adult rats during dehydration,” Brain Res., 829, No. 1–2, 7–17 (1999).PubMedCrossRefGoogle Scholar
  57. 57.
    E. Messi, M. C. Florian, C. Caccia, et al., “Retinoic acid reduces human neuroblastoma cell migration and invasiveness: effects on DCX, LIS1, neurofilaments-68 and vimentin expression,” BMC Cancer, 8, No. 30, 1–12 (2008).Google Scholar
  58. 58.
    C. A. Moores, M. Perderiset, F. Francis, et al., “Mechanism of microtubule stabilization by doublecortin,” Mol. Cell, 14, No. 6, 833–839 (2004).PubMedCrossRefGoogle Scholar
  59. 59.
    J. Nacher, C. Crespo, and B. S. McEwen, “Doublecortin expression in the adult rat telencephalon,” Eur. J. Neurosci., 14, No. 4, 629–644 (2001).PubMedCrossRefGoogle Scholar
  60. 60.
    T. Nakagomi, A. Taguchi, Y. Fujimori, et al., “Isolation and characterization of neural stem/progeny cells from post-stroke cerebral cortex neuron mice,” Eur. J. Neurosci., 29, No. 9, 1842–1852 (2009).PubMedCrossRefGoogle Scholar
  61. 61.
    L. Pietranera, A. Lima, and A. F. De Nicola, “Involvement of brainderived neurotrophic factor and neurogenesis in oestradiol neuroprotection of the hippocampus of hypertensive rats,” J. Neuroendocrinol., 22, No. 10, 1082–1092 (2010).PubMedCrossRefGoogle Scholar
  62. 62.
    I. Prajerova, P. Honsa, A. Chvatal, and M. Anderova, “Neural stem/progenitor cells derived from the embryonic dorsal telencephalon of D6/GFP mice differentiate primarily into neurons after transplantation into a cortical lesion,” Cell Mol. Neurobiol., 30, No. 2, 199–218 (2010).PubMedCrossRefGoogle Scholar
  63. 63.
    R. L. Ramos, J. Bai, and J. J. LoTurco, “Heterotopia formation in rat but not mouse neocortex after RNA interference knockdown of DCX,” Cereb. Cortex, 16, No. 9, 1323–1331 (2006).PubMedCrossRefGoogle Scholar
  64. 64.
    O. Reiner, F. M. Coquelle, B. Peter, et al., “The evolving doublecortin (DCX) superfamily,” BMC Genomics, 7, No. 188, 1–16 (2006).Google Scholar
  65. 65.
    H. M. Rubino, M. Dammerman, B. Shafit-Zagardo, and J. Erlichman, “Localization and characterization of the binding site for the regulatory subunit of type II cAMP-dependent protein kinase on MAP2,” Neuron, 3, No. 5, 631–638 (1989).PubMedCrossRefGoogle Scholar
  66. 66.
    C. Sánchez, J. Díaz-Nido, and J. Avila, “Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function,” Prog. Neurobiol., 61, No. 2, 133–168 (2000).PubMedCrossRefGoogle Scholar
  67. 67.
    R. K. Sharma and P. A. Netland, “Early born lineage of retinal neurons express class III beta-tubulin isotype,” Brain Res., 1176, 11–17 (2007).PubMedCrossRefGoogle Scholar
  68. 68.
    Y. Shen and L. C. Yu, “Potential protection of curcumin against hypoxia-induced decreases in beta-III tubulin content in rat prefrontal cortical neurons,” Neurochem. Res., 33, No. 10, 2112–2117 (2008).PubMedCrossRefGoogle Scholar
  69. 69.
    A. Shmueli, A. Gdalyahu, S. Sapoznik, et al., “Site-specific dephosphorylation of doublecortin (DCX) by protein phosphatase 1 (PP1),” Mol. Cell Neurosci., 32, No. 1, 15–26 (2006).PubMedCrossRefGoogle Scholar
  70. 70.
    D. Skoda, K. Kranda, M. Bojar, et al., “Antibody formation against beta-tubulin class III in response to brain trauma,” Brain Res. Bull., 68, No. 4, 213–216 (2006).PubMedCrossRefGoogle Scholar
  71. 71.
    K. F. Sullivan, “Structure and utilization of tubulin isotypes,” Annu. Rev. Cell Biol., 4, 687–716 (1988).PubMedCrossRefGoogle Scholar
  72. 72.
    J. Teng,Y. Takei, A. Harada, et al., “Synergistic effects of MAP2 and MAP1B knockout in neuronal migration, dendritic outgrowth, and microtubule organization,” J. Cell Biol., 155, No. 1, 65–76 (2001).PubMedCrossRefGoogle Scholar
  73. 73.
    R. P. Tucker and A. I. Matus, “Microtubule-associated proteins characteristic of embryonic brain are found in the adult mammalian retina,” Dev. Biol., 130, No. 2, 423–434 (1988).PubMedCrossRefGoogle Scholar
  74. 74.
    M. M. Valdivia, J. Avila, J. Coll, et al., “Quantitation and characterization of the microtubule associated MAP2 in porcine tissues and its isolation from porcine (PK15) and human (HeLa) cell lines,” Biochem. Biophys. Res. Commun., 105, No. 4, 1241–1249 (1982).PubMedCrossRefGoogle Scholar
  75. 75.
    C. Viereck, R. P. Tucker, and A. Matus, “The adult rat olfactory system expresses microtubule-associated proteins found in the developing brain,” J. Neurosci., 9, No. 10, 3547–3557 (1989).PubMedGoogle Scholar
  76. 76.
    H. Yamanouchi,V. Jay, H. Otsubo, et al., “Early forms of microtubulesassociated protein are strongly expressed in cortical dysplasia,” Acta Neuropathol., 95, No. 5, 466–470 (1998).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2012

Authors and Affiliations

  • D. E. Korzhevskii
    • 1
  • M. N. Karpenko
    • 1
  • O. V. Kirik
    • 1
  1. 1.Laboratory for the Functional Morphology of the Peripheral Nervous System (Director: Doctor of Medical Sciences D. E. Korzhevskii), department of General and Special Morphology, Research Institute Experimental Medicine, North-Western BranchRussian Academy of Medical SciencesSt. PetersburgRussia

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