TACE (ADAM17) inhibits Schwann cell myelination


Tumor necrosis factor-α–converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo. We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: TACE downregulation induces precocious myelination and hypermyelination in vitro.
Figure 2: In vitro hypermyelination is neuron-autonomous.
Figure 3: TACE inactivation in motor neurons leads to precocious myelination.
Figure 4: HB9-cre; Tacefl/fl mice are hypermyelinated during development.
Figure 5: HB9-cre; Tacefl/fl adult mice were hypermyelinated and Remak fibers were aberrantly ensheathed.
Figure 6: Mpz-cre; Tacefl/fl mice were normally myelinated.
Figure 7: TACE cleaves NRG1 type III.
Figure 8: TACE regulates NRG1 type III activity.


  1. 1

    Taveggia, C. et al. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47, 681–694 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Michailov, G.V. et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700–703 (2004).

    CAS  Article  Google Scholar 

  3. 3

    Willem, M. et al. Control of peripheral nerve myelination by the β-secretase BACE1. Science 314, 664–666 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Hu, X. et al. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB J. 22, 2970–2980 (2008).

    CAS  Article  Google Scholar 

  5. 5

    Hu, X. et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci. 9, 1520–1525 (2006).

    CAS  Article  Google Scholar 

  6. 6

    Yang, P., Baker, K.A. & Hagg, T. The ADAMs family: coordinators of nervous system development, plasticity and repair. Prog. Neurobiol. 79, 73–94 (2006).

    CAS  Article  Google Scholar 

  7. 7

    Shirakabe, K., Wakatsuki, S., Kurisaki, T. & Fujisawa-Sehara, A. Roles of Meltrin β/ADAM19 in the processing of neuregulin. J. Biol. Chem. 276, 9352–9358 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Yokozeki, T. et al. Meltrin beta (ADAM19) mediates ectodomain shedding of Neuregulin beta1 in the Golgi apparatus: fluorescence correlation spectroscopic observation of the dynamics of ectodomain shedding in living cells. Genes Cells 12, 329–343 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Wakatsuki, S., Yumoto, N., Komatsu, K., Araki, T. & Sehara-Fujisawa, A. Roles of meltrin-β/ADAM19 in progression of Schwann cell differentiation and myelination during sciatic nerve regeneration. J. Biol. Chem. 284, 2957–2966 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Sagane, K. et al. Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice. BMC Neurosci. 6, 33 (2005).

    Article  Google Scholar 

  11. 11

    Ozkaynak, E. et al. Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling. J. Neurosci. 30, 3857–3864 (2010).

    Article  Google Scholar 

  12. 12

    Freese, C., Garratt, A.N., Fahrenholz, F. & Endres, K. The effects of alpha-secretase ADAM10 on the proteolysis of neuregulin-1. FEBS J. 276, 1568–1580 (2009).

    CAS  Article  Google Scholar 

  13. 13

    Horiuchi, K., Zhou, H.M., Kelly, K., Manova, K. & Blobel, C.P. Evaluation of the contributions of ADAMs 9, 12, 15, 17, and 19 to heart development and ectodomain shedding of neuregulins β1 and β2. Dev. Biol. 283, 459–471 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Blobel, C.P. ADAMs: key components in EGFR signalling and development. Nat. Rev. Mol. Cell Biol. 6, 32–43 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Peschon, J.J. et al. An essential role for ectodomain shedding in mammalian development. Science 282, 1281–1284 (1998).

    CAS  Article  Google Scholar 

  16. 16

    Cosgaya, J.M., Chan, J.R. & Shooter, E.M. The neurotrophin receptor p75NTR as a positive modulator of myelination. Science 298, 1245–1248 (2002).

    CAS  Article  Google Scholar 

  17. 17

    Woodhoo, A. et al. Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat. Neurosci. 12, 839–847 (2009).

    CAS  Article  Google Scholar 

  18. 18

    Zampieri, N., Xu, C.F., Neubert, T.A. & Chao, M.V. Cleavage of p75 neurotrophin receptor by α-secretase and γ-secretase requires specific receptor domains. J. Biol. Chem. 280, 14563–14571 (2005).

    CAS  Article  Google Scholar 

  19. 19

    van Tetering, G. et al. Metalloprotease ADAM10 is required for Notch1 site 2 cleavage. J. Biol. Chem. 284, 31018–31027 (2009).

    CAS  Article  Google Scholar 

  20. 20

    Weber, S. et al. The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and Notch-mediated signaling. Development 138, 495–505 (2011).

    CAS  Article  Google Scholar 

  21. 21

    Horiuchi, K. et al. Cutting edge: TNF-α-converting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock. J. Immunol. 179, 2686–2689 (2007).

    CAS  Article  Google Scholar 

  22. 22

    Yang, X. et al. Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation. Neuron 30, 399–410 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Donald, D. A relation between axone diameter and myelination determined by measurement of myelinated spinal root fibers. J. Comp. Neurol. 60, 437–471 (1934).

    Article  Google Scholar 

  24. 24

    Windebank, A.J., Wood, P., Bunge, R.P. & Dyck, P.J. Myelination determines the caliber of dorsal root ganglion neurons in culture. J. Neurosci. 5, 1563–1569 (1985).

    CAS  Article  Google Scholar 

  25. 25

    Maurel, P. & Salzer, J.L. Axonal regulation of Schwann cell proliferation and survival and the initial events of myelination requires PI 3-kinase activity. J. Neurosci. 20, 4635–4645 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Ogata, T. et al. Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination. J. Neurosci. 24, 6724–6732 (2004).

    CAS  Article  Google Scholar 

  27. 27

    Schwenk, F., Baron, U. & Rajewsky, K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080–5081 (1995).

    CAS  Article  Google Scholar 

  28. 28

    Feltri, M.L. et al. Conditional disruption of β1 integrin in Schwann cells impedes interactions with axons. J. Cell Biol. 156, 199–209 (2002).

    CAS  Article  Google Scholar 

  29. 29

    Meyer, D. et al. Isoform-specific expression and function of neuregulin. Development 124, 3575–3586 (1997).

    CAS  PubMed  Google Scholar 

  30. 30

    Ohno, M. et al. Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system. Nat. Neurosci. 12, 1506–1513 (2009).

    CAS  Article  Google Scholar 

  31. 31

    Caescu, C.I., Jeschke, G.R. & Turk, B.E. Active-site determinants of substrate recognition by the metalloproteinases TACE and ADAM10. Biochem. J. 424, 79–88 (2009).

    CAS  Article  Google Scholar 

  32. 32

    Yang, H.C. et al. Biochemical and kinetic characterization of BACE1: investigation into the putative species-specificity for β- and β′-cleavage sites by human and murine BACE1. J. Neurochem. 91, 1249–1259 (2004).

    CAS  Article  Google Scholar 

  33. 33

    Thinakaran, G. & Koo, E.H. Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283, 29615–29619 (2008).

    CAS  Article  Google Scholar 

  34. 34

    Schlöndorff, J., Becherer, J.D. & Blobel, C.P. Intracellular maturation and localization of the tumour necrosis factor α convertase (TACE). Biochem. J. 347, 131–138 (2000).

    Article  Google Scholar 

  35. 35

    Doedens, J.R. & Black, R.A. Stimulation-induced down-regulation of tumor necrosis factor-α converting enzyme. J. Biol. Chem. 275, 14598–14607 (2000).

    CAS  Article  Google Scholar 

  36. 36

    Tellier, E. et al. The shedding activity of ADAM17 is sequestered in lipid rafts. Exp. Cell Res. 312, 3969–3980 (2006).

    CAS  Article  Google Scholar 

  37. 37

    Frenzel, K.E. & Falls, D.L. Neuregulin-1 proteins in rat brain and transfected cells are localized to lipid rafts. J. Neurochem. 77, 1–12 (2001).

    CAS  Article  Google Scholar 

  38. 38

    Koo, E.H. & Squazzo, S.L. Evidence that production and release of amyloid β-protein involves the endocytic pathway. J. Biol. Chem. 269, 17386–17389 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Burgess, T.L., Ross, S.L., Qian, Y.X., Brankow, D. & Hu, S. Biosynthetic processing of neu differentiation factor. Glycosylation trafficking, and regulated cleavage from the cell surface. J. Biol. Chem. 270, 19188–19196 (1995).

    CAS  Article  Google Scholar 

  40. 40

    Haass, C., Koo, E.H., Mellon, A., Hung, A.Y. & Selkoe, D.J. Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357, 500–503 (1992).

    CAS  Article  Google Scholar 

  41. 41

    Bozkulak, E.C. & Weinmaster, G. Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling. Mol. Cell. Biol. 29, 5679–5695 (2009).

    CAS  Article  Google Scholar 

  42. 42

    Buser, A.M. et al. The myelin protein MAL affects peripheral nerve myelination: a new player influencing p75 neurotrophin receptor expression. Eur. J. Neurosci. 29, 2276–2290 (2009).

    CAS  Article  Google Scholar 

  43. 43

    Tomita, K. et al. The neurotrophin receptor p75NTR in Schwann cells is implicated in remyelination and motor recovery after peripheral nerve injury. Glia 55, 1199–1208 (2007).

    Article  Google Scholar 

  44. 44

    Fricker, F.R. et al. Sensory axon-derived neuregulin-1 is required for axoglial signaling and normal sensory function but not for long-term axon maintenance. J. Neurosci. 29, 7667–7678 (2009).

    CAS  Article  Google Scholar 

  45. 45

    Fricker, F.R. et al. Axonally derived neuregulin-1 is required for remyelination and regeneration after nerve injury in adulthood. J. Neurosci. 31, 3225–3233 (2011).

    CAS  Article  Google Scholar 

  46. 46

    Moss, M.L., Sklair-Tavron, L. & Nudelman, R. Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 4, 300–309 (2008).

    CAS  Article  Google Scholar 

  47. 47

    Maurel, P. et al. Nectin-like proteins mediate axon Schwann cell interactions along the internode and are essential for myelination. J. Cell Biol. 178, 861–874 (2007).

    CAS  Article  Google Scholar 

  48. 48

    Quattrini, A. et al. β4 integrin and other Schwann cell markers in axonal neuropathy. Glia 17, 294–306 (1996).

    CAS  Article  Google Scholar 

  49. 49

    Shevchenko, A., Wilm, M., Vorm, O. & Mann, M. Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal. Chem. 68, 850–858 (1996).

    CAS  Article  Google Scholar 

  50. 50

    Wrabetz, L. et al. A minimal human MBP promoter-lacZ transgene is appropriately regulated in developing brain and after optic enucleation, but not in shiverer mutant mice. J. Neurobiol. 34, 10–26 (1998).

    CAS  Article  Google Scholar 

Download references


We thank S. Arber (University of Basel) for providing the HB9-cre transgenic line, M. Filbin (Hunter College) for antibodies, P. Podini for assistance with electron microscopy, G. Dina and A. Cattaneo for technical support and Y. Poitelon for artwork. This study was supported by the Federazione Italiana Sclerosi Multipla (FISM) (grant 2007/PC/01) and the Compagnia di San Paolo (C.T.); by the US National Institute of Health (grants R01-NS045630 (M.L.F.), R01-NS055256 (L.W.), R01-GM64750 (C.P.B.) and RO1-NS26001 (J.L.S.)); by Telethon Italia (grants GGP08021 (M.L.F.), GGP071100 (L.W.) and GPP10007 (C.T., L.W. and M.L.F.)). C.T. is a recipient of a FISM Transition Career Award.

Author information




R.L.M. conducted most of the experiments. F.C. and A.Q. performed morphological and ultrastructural analyses of sciatic nerves and ventral roots. K.H., C.P.B., M.L.F. and L.W. provided transgenic lines and helped with discussions. A.B. performed the mass spectrometry analyses. J.L.S. provided support and initially contributed to the experimental design. C.T. designed the experimental plan, supervised the project and wrote the paper. All authors commented on the paper.

Corresponding author

Correspondence to Carla Taveggia.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Table 1 (PDF 6622 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

La Marca, R., Cerri, F., Horiuchi, K. et al. TACE (ADAM17) inhibits Schwann cell myelination. Nat Neurosci 14, 857–865 (2011). https://doi.org/10.1038/nn.2849

Download citation

Further reading


Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing