The pathogenesis of peripheral neuropathies in adults is linked to maintenance mechanisms that are not well understood. Here, we elucidate a novel critical maintenance mechanism for Schwann cell (SC)–axon interaction. Using mouse genetics, ablation of the transcriptional regulators histone deacetylases 1 and 2 (HDAC1/2) in adult SCs severely affected paranodal and nodal integrity and led to demyelination/remyelination. Expression levels of the HDAC1/2 target gene myelin protein zero (P0) were reduced by half, accompanied by altered localization and stability of neurofascin (NFasc)155, NFasc186, and loss of Caspr and septate-like junctions. We identify P0 as a novel binding partner of NFasc155 and NFasc186, both in vivo and by in vitro adhesion assay. Furthermore, we demonstrate that HDAC1/2-dependent P0 expression is crucial for the maintenance of paranodal/nodal integrity and axonal function through interaction of P0 with neurofascins. In addition, we show that the latter mechanism is impaired by some P0 mutations that lead to late onset Charcot-Marie-Tooth disease.
References
[1]
Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG. Molecular changes in neurons in multiple sclerosis: altered axonal expression of NaV1.2 and NaV1.6 sodium channels and Na+/Ca+ exchanger. Proc Natl Acad Sci USA. 2004;101: 8168–8173. pmid:15148385 doi: 10.1073/pnas.0402765101
[2]
Mathey EK, Derfuss T, Storch MK, Williams KR, Hales K, Woolley DR, et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med. 2007;204: 2363–2372. pmid:17846150 doi: 10.1084/jem.20071053
[3]
Susuki K, Rasband MN, Tohyama K, Koibuchi K, Okamoto S, Funakoshi K, et al. Anti-GM1 antibodies cause complement-mediated disruption of sodium channel clusters in peripheral motor nerve fibers. J Neurosci. 2007;27: 3956–3967. pmid:17428969 doi: 10.1523/jneurosci.4401-06.2007
[4]
Devaux JJ, Odaka M, Yuki N. Nodal proteins are target antigens in Guillain-Barré syndrome. J Peripher Nerv Syst. 2012;17: 62–71. doi: 10.1111/j.1529-8027.2012.00372.x. pmid:22462667
[5]
Meadows LS, Malhotra J, Loukas A, Thyagarajan V, Kazen-Gillespie KA, Koopman MC, et al. Functional and biochemical analysis of a sodium channel beta1 subunit mutation responsible for generalized epilepsy with febrile seizures plus type 1. J Neurosci. 2002;22: 10699–10709. pmid:12486163
[6]
Cruz DA, Weaver CL, Lovallo EM, Melchitzky DS, Lewis DA. Selective alterations in postsynaptic markers of chandelier cell inputs to cortical pyramidal neurons in subjects with schizophrenia. Neuropsychopharmacology 2009;34: 2112–2124. doi: 10.1038/npp.2009.36. pmid:19322171
[7]
Salzer JL, Brophy PJ, Peles E. Molecular domains of myelinated axons in the peripheral nervous system. Glia. 2008;56: 1532–1540. doi: 10.1002/glia.20750. pmid:18803321
[8]
Buttermore ED, Thaxton CL, Bhat MA. Organization and maintenance of molecular domains in myelinated axons. J Neurosci Res. 2013;91: 603–622. doi: 10.1002/jnr.23197. pmid:23404451
[9]
Eshed-Eisenbach Y, Peles E. The making of a node: a co-production of neurons and glia. Curr Opin Neurobiol. 2013;23: 1049–1056. doi: 10.1016/j.conb.2013.06.003. pmid:23831261
[10]
de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370: 737–749. pmid:12429021 doi: 10.1042/bj20021321
[11]
Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J. 2007;404: 1–13. pmid:17447894 doi: 10.1042/bj20070140
[12]
Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone proteins. Gene. 2005;363: 15–23. pmid:16289629 doi: 10.1016/j.gene.2005.09.010
[13]
Yao YL, Yang WM. Beyond histone and deacetylase: an overview of cytoplasmic histone deacetylases and their non-histone substrates. J Biomed Biotechnol. 2011;2011: 146493. doi: 10.1155/2011/146493. pmid:21234400
[14]
Jacob C, L？tscher P, Engler S, Baggiolini A, Varum Tavares S, Brügger V, et al. HDAC1 and HDAC2 control the specification of neural crest cells into peripheral glia. J Neurosci. 2014;34: 6112–6122. doi: 10.1523/JNEUROSCI.5212-13.2014. pmid:24760871
[15]
Jacob C, Christen CN, Pereira JA, Somandin C, Baggiolini A, L？tscher P, et al. HDAC1 and HDAC2 control the transcriptional program of myelination and the survival of Schwann cells. Nat Neurosci. 2011;14: 429–436. doi: 10.1038/nn.2762. pmid:21423190
[16]
Jacob C, Lebrun-Julien F, Suter U. How histone deacetylases control myelination. Mol Neurobiol. 2011;44: 303–312. doi: 10.1007/s12035-011-8198-9. pmid:21861092
[17]
Chen Y, Wang H, Yoon SO, Xu X, Hottiger MO, Svaren J, et al. HDAC-mediated deacetylation of NF-κB is critical for Schwann cell myelination. Nat Neurosci. 2011;14: 437–441. doi: 10.1038/nn.2780. pmid:21423191
[18]
Shapiro L, Doyle JP, Hensley P, Colman DR, Hendrickson WA. Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin. Neuron. 1996;17: 435–449. pmid:8816707 doi: 10.1016/s0896-6273(00)80176-2
[19]
Shy ME, Jáni A, Krajewski K, Grandis M, Lewis RA, Li J, et al. Phenotypic clustering in MPZ mutations. Brain. 2004;127: 371–384. pmid:14711881 doi: 10.1093/brain/awh048
[20]
Leone DP, Genoud S, Atanasoski S, Grausenburger R, Berger P, Metzger D, et al. Tamoxifen-inducible glia-specific Cre mice for somatic mutagenesis in oligodendrocytes and Schwann cells. Mol Cell Neurosci. 2003;22: 430–440. pmid:12727441 doi: 10.1016/s1044-7431(03)00029-0
[21]
Yamaguchi T, Cubizolles F, Zhang Y, Reichert N, Kohler H, Seiser C, et al. Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. Genes Dev. 2010;24: 455–469. doi: 10.1101/gad.552310. pmid:20194438
[22]
Ribeiro S, Napoli I, White IJ, Parrinello S, Flanagan AM, Suter U, et al. Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve. Cell Rep. 2013;5: 126–136. doi: 10.1016/j.celrep.2013.08.033. pmid:24075988
[23]
Montgomery RL, Davis CA, Potthoff M, Haberland M, Fielitz J, Qi X, et al. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 2007;21: 1790–1802. pmid:17639084 doi: 10.1101/gad.1563807
[24]
Ye F, Chen Y, Hoang T, Montgomery RL, Zhao XH, Bu H, et al. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the β-catenin–TCF interaction. Nat Neurosci. 2009;12: 829–838. doi: 10.1038/nn.2333. pmid:19503085
[25]
Bhat MA, Rios JC, Lu Y, Garcia-Fresco GP, Ching W, St. Martin M, et al. Axon-glia interactions and the domain organization of myelinated axons requires NeurexinIV/Caspr/Paranodin. Neuron. 2001;30: 369–383. pmid:11395000 doi: 10.1016/s0896-6273(01)00294-x
[26]
Colombelli C, Palmisano M, Eshed-Eisenbach Y, Zambroni D, Pavoni E, Ferri C, et al. Perlecan is recruited by dystroglycan to nodes of Ranvier and binds the clustering molecule gliomedin. J Cell Biol. 2015; 208: 313–329. doi: 10.1083/jcb.201403111. pmid:25646087
[27]
Tait S, Gunn-Moore F, Collinson JM, Huang J, Lubetzki C, Pedraza L, et al. An oligodendrocyte cell adhesion molecule at the site of assembly of the paranodal axo-glial junction. J Cell Biol. 2000;150: 657–666. pmid:10931875 doi: 10.1083/jcb.150.3.657
[28]
Rios JC, Melendez-Vasquez CV, Einheber S, Lustig M, Grumet M, Hemperly J, et al. Contactin-associated protein (Caspr) and contactin form a complex that is targeted to the paranodal junctions during myelination. J Neurosci. 2000;20: 8354–8364. pmid:11069942
[29]
Boyle MET, Berglund EO, Murai KK, Weber L, Peles E, Ranscht B. Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron. 2001;30: 385–397. pmid:11395001 doi: 10.1016/s0896-6273(01)00296-3
[30]
Charles P, Tait S, Faivre-Sarrailh C, Barbin G, Gunn-Moore F, Denisenko-Nehrbass N, et al. Neurofascin is a glial receptor for the Paranodin/Caspr-Contactin axonal complex at the axoglial junction. Curr Biol. 2002;12: 217–220. pmid:11839274 doi: 10.1016/s0960-9822(01)00680-7
[31]
Sherman DL, Tait S, Melrose S, Johnson R, Zonta B, Court FA, et al. Neurofascins are required to establish axonal domains for saltatory conduction. Neuron. 2005;48: 737–742. pmid:16337912 doi: 10.1016/j.neuron.2005.10.019
[32]
Martini R, Zielasek J, Toyka KV, Giese KP, Schachner M. Protein zero (P0)-deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies. Nat Genet. 1995;11: 281–286. pmid:7581451 doi: 10.1038/ng1195-281
[33]
Samsam M, Frei R, Marziniak M, Martini R, Sommer C. Impaired sensory function in heterozygous P0 knockout mice is associated with nodal changes in sensory nerves. J Neurosci Res. 2002;67: 167–173. pmid:11782960 doi: 10.1002/jnr.10115
[34]
Ulzheimer JC, Peles E, Levinson SR, Martini R. Altered expression of ion channel isoforms at the node of Ranvier in P0-deficient myelin mutants. Mol Cell Neurosci. 2004;25: 83–94. pmid:14962742 doi: 10.1016/j.mcn.2003.09.015
[35]
Fratta P, Saveri P, Zambroni D, Ferri C, Tinelli E, Messing A, et al. P0S63del impedes the arrival of wild-type P0 glycoprotein to myelin in CMT1B mice. Hum Mol Genet. 2001;20: 2081–2090. doi: 10.1093/hmg/ddr081
[36]
Pillai AM, Thaxton C, Pribisko AL, Cheng Jr-G, Dupree JL, Bhat MA. Spatiotemporal ablation of myelinating glia-specific neurofascin (NfascNF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains. J Neurosci Res. 2009;87: 1773–1793. doi: 10.1002/jnr.22015. pmid:19185024
[37]
Mastaglia FL, Nowak KJ, Stell R, Phillips BA, Edmondston JE, Dorosz SM, et al. Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy. J Neurol Neurosurg Psychiatry 1999;67: 174–179. pmid:10406984 doi: 10.1136/jnnp.67.2.174
[38]
Senderek J, Hermanns B, Lehmann U, Bergmann C, Marx G, Kabus C, et al. Charcot-Marie-Tooth neuropathy type 2 and P0 point mutations: two novel amino acid substitutions (Asp61Gly; Tyr119Cys) and a possible “hotspot” on Thr124Met. Brain Pathology. 2000;10: 235–248. pmid:10764043 doi: 10.1111/j.1750-3639.2000.tb00257.x
[39]
Bienfait HME, Baas F, Gabre？ls-Festen AAWM, Koelman JHTM, Langerhorst CT, de Visser M, et al. Two amino-acid substitutions in the myelin protein zero gene of a case of Charcot–Marie–Tooth disease associated with light-near dissociation. Neuromuscular Disorders. 2002;12: 281–285. pmid:11801400 doi: 10.1016/s0960-8966(01)00281-4
[40]
Silander K, Meretoja P, Juvonen Vesa, Ignatius Jaakko, Pihko Helena, Saarinen Ari, et al. Spectrum of mutations in Finnish patients with Charcot-Marie-Tooth disease and related neuropathies. Human Mutation. 1998;12: 59–68. pmid:9633821 doi: 10.1002/(sici)1098-1004(1998)12:1<59::aid-humu9>3.0.co;2-a
[41]
Fabrizi GM, Taioli F, Cavallaro T, Rigatelli F, Simonati A, Mariani G, et al. Focally folded myelin in Charcot-Marie-Tooth neuropathy type 1B with Ser49Leu in the myelin protein zero. Acta Neuropathol. 2000;100: 299–304. pmid:10965800 doi: 10.1007/s004019900175
[42]
Thaxton C, Pillai AM, Pribisko AL, Dupree JL, Bhat MA. Nodes of Ranvier act as barriers to restrict invasion of flanking paranodal domains in myelinated axons. Neuron. 2011;69: 244–257. doi: 10.1016/j.neuron.2010.12.016. pmid:21262464
[43]
Amor V, Feinberg K, Eshed-Eisenbach Y, Vainshtein A, Frechter S, Grumet M, et al. Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM. J Neurosci. 2014;34: 5089–5098. doi: 10.1523/JNEUROSCI.4752-13.2014. pmid:24719088
[44]
Eshed Y, Feinberg K, Poliak S, Sabanay H, Sarig-Nadir O, Spiegel I, et al. Gliomedin mediates Schwann cell-axon interaction and the molecular assembly of the nodes of Ranvier. Neuron. 2005;47: 215–229. pmid:16039564 doi: 10.1016/j.neuron.2005.06.026
[45]
Kriebel M, Wuchter J, Trinks S, Volkmer H. Neurofascin: a switch between neuronal plasticity and stability. Int J Biochem Cell Biol. 2012;44: 694–697. doi: 10.1016/j.biocel.2012.01.012. pmid:22306302
[46]
Giese KP, Martini R, Lemke G, Soriano P, Schachner M. Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell. 1992;71: 565–576. pmid:1384988 doi: 10.1016/0092-8674(92)90591-y
[47]
Guo W, Keckesova Z, Donaher JL, Shibue T, Tischler V, Reinhardt F, et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell. 2012;148: 1015–1028. doi: 10.1016/j.cell.2012.02.008. pmid:22385965
[48]
Szulc J, Wiznerowicz M, Sauvain MO, Trono D, Aebischer P. A versatile tool for conditional gene expression and knockdown. Nat Methods. 2006;3: 109–116. pmid:16432520 doi: 10.1038/nmeth846
[49]
Zhang X, Davis JQ, Carpenter S, Bennett V. Structural requirements for association of neurofascin with ankyrin. J Biol Chem. 1998;273: 30785–30794. pmid:9804856 doi: 10.1074/jbc.273.46.30785
[50]
Pereira JA, Benninger Y, Baumann R, Gon？alves AF, ？z？elik M, Thurnherr T, et al. Integrin-linked kinase is required for radial sorting of axons and Schwann cell remyelination in the peripheral nervous system. J Cell Biol. 2009;185: 147–161. doi: 10.1083/jcb.200809008. pmid:19349584
[51]
Jacob C, Grabner H, Atanasoski S, Suter U. Expression and localization of Ski determine cell type-specific TGFβ signaling effects on the cell cycle. J Cell Biol. 2008;182: 519–530. doi: 10.1083/jcb.200710161. pmid:18695043
[52]
Paratore C, Suter U, Sommer L. Embryonic gene expression resolved at the cellular level by fluorescence in situ hybridization. Histochem Cell Biol. 1999;111: 435–443. pmid:10429965 doi: 10.1007/s004180050379
[53]
Stendel C, Roos A, Kleine H, Arnaud E, Oz？elik M, Sidiropoulos PN, et al. SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling. Brain. 2010;133: 2462–2474. doi: 10.1093/brain/awq168. pmid:20826437
[54]
Brügger V, Engler S, Pereira JA, Ruff S, Horn M, Welzl H, et al. (2015) Data from: HDAC1/2-Dependent P0 Expression Maintains Paranodal and Nodal Integrity Independently of Myelin Stability through Interactions with Neurofascins. Dryad Digital Repository. Openly available via .
