Neurochemical Research

, Volume 32, Issue 2, pp 187–195 | Cite as

Microtubule Deacetylases, SirT2 and HDAC6, in the Nervous System

  • Cherie M. Southwood
  • Marcello Peppi
  • Sylvia Dryden
  • Michael A. Tainsky
  • Alexander Gow


Examination of the cytoskeleton has demonstrated the pivotal role of regulatory proteins governing cytoskeletal dynamics. Most work has focused on cell cycle and cell migration regarding cancer. However, these studies have yielded tremendous insight for development, particularly in the nervous system where all major cell types remodel their shape, generate unsurpassed quantities of membranes and extend cellular processes to communicate, and regulate the activities of other cells. Herein, we analyze two microtubule regulatory alpha-tubulin deacetylases, histone deacetylase-6 (HDAC6) and SirT2. HDAC6 is expressed by most neurons but is abundant in cerebellar Purkinje cells. In contrast, SirT2 is targeted to myelin sheaths. Expression of these proteins by post-mitotic cells indicates novel functions, such as process outgrowth and membrane remodeling. In oligodendrocytes, targeting of SirT2 to paranodes coincides with the presence of the microtubule-destabilizing protein stathmin-1 during early myelinogenesis and suggests the existence of a microtubule regulatory network that modulates cytoskeletal dynamics.


Axoglial junctions Myelinated fibers Central nervous system Peripheral nervous system Immunofluorescence Mouse 



This work was supported by grants to A.G. from NINDS, NIH (NS43783) and the National Multiple Sclerosis Society (RG2891).


  1. 1.
    Knobler RL, Stempak JG, Laurencin M (1974) Oligodendroglial ensheathment of axons during myelination in the developing rat central nervous system. A serial section electron microscopical study. J Ultrastruct Res 49(1):34–49PubMedCrossRefGoogle Scholar
  2. 2.
    Xin M, Yue T, Ma Z, Wu FF, Gow A, Lu QR (2005) Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1-null mice. J Neurosci 25(6):1354–1365PubMedCrossRefGoogle Scholar
  3. 3.
    Southwood C, He C, Garbern J, Kamholz J, Arroyo E, Gow A (2004) CNS myelin paranodes require Nkx6-2 homeoprotein transcriptional activity for normal structure. J Neurosci 24(50):11215–11225PubMedCrossRefGoogle Scholar
  4. 4.
    Suter U, Scherer SS (2003) Disease mechanisms in inherited neuropathies. Nat Rev Neurosci 4(9):714–726PubMedCrossRefGoogle Scholar
  5. 5.
    Salzer JL (2003) Polarized domains of myelinated axons. Neuron 40(2):297–318PubMedCrossRefGoogle Scholar
  6. 6.
    Bhat MA (2003) Molecular organization of axo-glial junctions. Curr Opin Neurobiol 13(5):552–559PubMedCrossRefGoogle Scholar
  7. 7.
    Ozon S, Guichet A, Gavet O, Roth S, Sobel A (2002) Drosophila stathmin: a microtubule-destabilizing factor involved in nervous system formation. Mol Biol Cell 13(2):698–710PubMedCrossRefGoogle Scholar
  8. 8.
    Andersen SS (2000) Spindle assembly and the art of regulating microtubule dynamics by MAPs and Stathmin/Op18. Trends Cell Biol 10(7):261–267PubMedCrossRefGoogle Scholar
  9. 9.
    Liedtke W, Leman EE, Fyffe RE, Raine CS, Schubart UK (2002) Stathmin-deficient mice develop an age-dependent axonopathy of the central and peripheral nervous systems. Am J Pathol 160(2):469–480PubMedGoogle Scholar
  10. 10.
    Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA (2003) Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol 23(9):3173–3185PubMedCrossRefGoogle Scholar
  11. 11.
    North BJ, Marshall BL, Borra MT, Denu JM, Verdin E (2003) The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 11(2):437–444PubMedCrossRefGoogle Scholar
  12. 12.
    Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417(6887):455–458PubMedCrossRefGoogle Scholar
  13. 13.
    Frye RA (1999) Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun 260(1):273–279PubMedCrossRefGoogle Scholar
  14. 14.
    Yamamura T, Konola JT, Wekerle H, Lees MB (1991) Monoclonal antibodies against myelin proteolipid protein: identification and characterization of two major determinants. J Neurochem 57:1671–1680PubMedCrossRefGoogle Scholar
  15. 15.
    Bhat MA, Rios JC, Lu Y, Garcia-Fresco GP, Ching W, Martin MS, Li J, Einheber S, Chesler M, Rosenbluth J, Salzer JL, Bellen HJ (2001) Axon-glia interactions and the domain organization of myelinated axons requires neurexin iv/caspr/paranodin. Neuron 30(2):369–383PubMedCrossRefGoogle Scholar
  16. 16.
    Gow A, Davies C, Southwood CM, Frolenkov G, Chrustowski M, Ng L, Yamauchi D, Marcus DM, Kachar B (2004) Deafness in Claudin 11-null mice reveals the critical contribution of basal cell tight junctions to stria vascularis function. J Neurosci 24(32):7051–7062PubMedCrossRefGoogle Scholar
  17. 17.
    Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ (1979) Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18(24):5294–5299PubMedCrossRefGoogle Scholar
  18. 18.
    Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning. A laboratory manual. Cold Spring Harbor Press, New YorkGoogle Scholar
  19. 19.
    Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685PubMedCrossRefGoogle Scholar
  20. 20.
    Sorg BA, Smith MM, Campagnoni AT (1987) Developmental expression of the myelin proteolipid protein and basic protein mRNAs in normal and dysmyelinating mutant mice. J Neurochem 49(4):1146–1154PubMedCrossRefGoogle Scholar
  21. 21.
    Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang Y, Li N, Caron C, Matthias G, Hess D, Khochbin S, Matthias P (2003) HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. Embo J 22(5):1168–1179PubMedCrossRefGoogle Scholar
  23. 23.
    Song J, Goetz BD, Baas PW, Duncan ID (2001) Cytoskeletal reorganization during the formation of oligodendrocyte processes and branches. Mol Cell Neurosci 17(4):624–636PubMedCrossRefGoogle Scholar
  24. 24.
    Westermann S, Weber K (2003) Post-translational modifications regulate microtubule function. Nat Rev Mol Cell Biol 4(12):938–947PubMedCrossRefGoogle Scholar
  25. 25.
    Tanner KG, Landry J, Sternglanz R, Denu JM (2000) Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc Natl Acad Sci USA 97(26):14178–14182PubMedCrossRefGoogle Scholar
  26. 26.
    Bedalov A, Simon JA (2003) Sir2 flexes its muscle. Dev Cell 5(2):188–189PubMedCrossRefGoogle Scholar
  27. 27.
    Fulco M, Schiltz RL, Iezzi S, King MT, Zhao P, Kashiwaya Y, Hoffman E, Veech RL, Sartorelli V (2003) Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol Cell 12(1):51–62PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Cherie M. Southwood
    • 1
  • Marcello Peppi
    • 1
  • Sylvia Dryden
    • 2
  • Michael A. Tainsky
    • 1
    • 2
    • 3
  • Alexander Gow
    • 1
    • 4
    • 5
  1. 1.Center for Molecular Medicine and GeneticsWayne State University School of MedicineDetroitUSA
  2. 2.Karmanos Cancer CenterWayne State University School of MedicineDetroitUSA
  3. 3.Department of PathologyWayne State University School of MedicineDetroitUSA
  4. 4.Carman and Ann Adams Department of PediatricsWayne State University School of MedicineDetroitUSA
  5. 5.Department of NeurologyWayne State University School of MedicineDetroitUSA

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