Skip to main content
Log in

Terminal Schwann cells guide the reinnervation of muscle after nerve injury

  • Published:
Journal of Neurocytology

Abstract

Schwann cells and axons labeled by transgene-encoded, fluorescent proteins can be repeatedly imaged in living mice to observe the reinnervation of neuromuscular junctions. Axons typically return to denervated junctions by growing along Schwann cells contained in the old nerve sheaths or “Schwann cell tubes”. These axons then commonly “escape” the synaptic sites by growing along the Schwann cell processes extended during the period of denervation. These “escaped fibers” grow to innervate adjacent synaptic sites along Schwann cells bridging these sites. Within the synaptic site, Schwann cells, originally positioned above the synaptic site continue to cover the acetylcholine receptors (AChRs) immediately following denervation, but gradually vacate portions of this site. When regenerating axons return, they first deploy along the Schwann cells and ignore sites of AChRs vacated by Schwann cells. In many cases these vacated sites are never reinnervated and are ultimately lost. Following partial denervation, Schwann cells grow in an apparently tropic fashion from denervated to nearby innervated synaptic sites and serve as the substrates for nerve sprouting. These experiments show that Schwann cells provide pathways that stimulate axon growth and insure the rapid reinnervation of denervated or partially denervated muscles.

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.

Institutional subscriptions

Similar content being viewed by others

References

  • ANTON, E. S., WESKAMP, G., REICHARDT, L. F. & MATTHEW, W. D. (1994) Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc. Natl. Acad. Sci. USA 91, 279–2799.

    PubMed  Google Scholar 

  • ASTROW, S. H., QIANG, H. & KO, C. P. (1998) Perisynaptic Schwann cells at neuromuscular junctions revealed by a novel monoclonal antibody. J. Neurocytol. 27, 66–681.

    PubMed  Google Scholar 

  • ASTROW, S. H., SON, Y.-J. & THOMPSON, W. J. (1994) Differential neural regulation of a neuromuscular junction-associated antigen in muscle fibers and Schwann cells. J. Neurobiol. 25, 93–952.

    PubMed  Google Scholar 

  • BALICE-GORDON, R. J. & LICHTMAN, J. W. (1994) Long-term synapse loss induced by focal blockade of postsynaptic receptors. Nature 372, 51–524.

    PubMed  Google Scholar 

  • BIRKS, R., HUXLEY, H. E. & KATZ, B. (1960a) The fine structure of the neuromuscular junction of the frog. J. Physiol. 150, 13–144.

    PubMed  Google Scholar 

  • BIRKS, R., KATZ, B. & MILEDI, R. (1960b) Physiological and structural changes at the amphibian myoneural junction, in the course of nerve degeneration. J. Physiol. 150, 14–168.

    PubMed  Google Scholar 

  • BIXBY, J. L., LILIEN, J. & REICHARDT, L. F. (1988) Identification of the major proteins that promote neuronal process outgrowth on Schwann cells in vitro. J. Cell Biol. 107, 35–361.

    PubMed  Google Scholar 

  • BRITSCH, S., GOERICH, D. E., RIETHMACHER, D., PEIRANO, R. I., ROSSNER, M., NAVE, K. A., BIRCHMEIER, C. & WEGNER, M. (2001) The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev. 15, 6–78.

    PubMed  Google Scholar 

  • BROCKES, J. P. (1984) Assays for cholinergic properties in cultured rat Schwann cells. Proc.Roy. Soc. Lond. B 222, 12–134.

    Google Scholar 

  • BROOKE, M. H., WILLIAMSON, E. & KAISER, K. K. (1971) The behavior of four fiber types in developing and reinnervated muscle. Arch. Neurol. 25, 36–366.

    PubMed  Google Scholar 

  • BROWN, M. C., HOLLAND, R. L. & HOPKINS, W. G. (1981) Motor nerve sprouting. Ann. Rev. Neurosci. 4, 1–42.

    PubMed  Google Scholar 

  • CASTETS, F., GRIFFIN, W. S. T., MARKS, A. & VAN ELDIK, L. J. (1997) Transcriptional regulation of the human S100? gene. Mol. Brain Res. 46, 20–216.

    PubMed  Google Scholar 

  • COUTEAUX, R. (1960) Motor end-plate structure. In The Structure and Function of Muscle (edited by BOURNE, G. H.) pp. 33–380. New York: Academic Press.

    Google Scholar 

  • DENNIS, M. J. & MILEDI, R. (1974) Electrically induced release of acetylcholine from denervated Schwann cells. J. Physiol. 237, 43–452.

    PubMed  Google Scholar 

  • DONG, Z., BRENNAN, A., LIU, N., YARDEN, Y., LEFKOWITZ, G., MIRSKY, R. & JESSEN, K. R. (1995) Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors. Neuron 15, 58–596.

    PubMed  Google Scholar 

  • FALLON, J. R. (1985) Neurite guidance by non-neuronal cells in culture: Preferential outgrowth of peripheral neurites on glial as compared to nonglial cell surfaces. J. Neurosci. 5, 316–3177.

    PubMed  Google Scholar 

  • FENG, G., MELLOR, R. H., BERNSTEIN, M., KELLERPECK, C., NGUYEN, Q. T., WALLACE, M., NERBONNE, J. M., LICHTMAN, J. W. & SANES, J. R. (2000) Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 4–51.

    PubMed  Google Scholar 

  • GUTMANN, E. & YOUNG, J. Z. (1944) The re-innervation of muscle after various periods of atrophy. J. Anat. 78, 1–43.

    Google Scholar 

  • HENDERSON, C. E., PHILLIPS, H. S., POLLOCK, R. A., DAVIES, A. M., LEMEULLE, C., ARMANINI, M., SIMPSON, L. C., MOFFET, B., VANDLEN, R. A., KOLIATSOS, V. E. & ROSENTHAL, A. (1994) GDNF:Apotent survival factor for motoneurons present in peripheral nerve and muscle. Science 266, 106– 1064.

    PubMed  Google Scholar 

  • HOLMES, W. & YOUNG, J. Z. (1942) Nerve regeneration after immediate and delayed suture. J. Anat. 77, 6–96.

    Google Scholar 

  • JAHROMI, B. S., ROBITAILLE, R. & CHARLTON, M. P. (1992) Transmitter release increases intracellular calcium in perisynaptic Schwann cells in situ. Neuron 8, 106–1077.

    PubMed  Google Scholar 

  • JIRMANOVÁ, I. (1975) Ultrastructure of motor end-plates during pharmacologically-induced degeneration and subsequent regeneration of skeletal muscle. J. Neurocytol. 4, 14–155.

    PubMed  Google Scholar 

  • KANG, H., LUBISCHER, J. L., NEWMAN, C. S., THOMPSON, W. J. & KRIEG, P. A. (2000) In vivo imaging of terminal Schwann cells using GFP expressing transgenic mice. Soc. Neurosci. Abs. 26, 703.2.

    Google Scholar 

  • KANG, H. & THOMPSON, W. J. (2002) Schwann cell processes guide axons reinnervating the neuromuscular junction. Soc. Neurosci. Abs. 28, 234.16.

    Google Scholar 

  • KO, C.-P. & CHEN, L. (1996) Synaptic remodeling revealed by repeated in vivo observations and electron microscopy of identified frog neuromuscular junctions. J. Neurosci. 16, 178–1790.

    PubMed  Google Scholar 

  • KOIRALA, S., QIANG, H. & KO, C. P. (2000) Reciprocal interactions between perisynaptic Schwann cells and regenerating nerve terminals at the frog neuromuscular junction. J. Neurobiol. 44, 34–360.

    PubMed  Google Scholar 

  • KUFFLER, S. W. & NICHOLLS, J. G. (1966) The physiology of neuroglial cells. Ergeb. Physiol. 57, –90.

    PubMed  Google Scholar 

  • LICHTMAN, J. W., MAGRASSI, L. & PURVES, D. (1987) Visualization of neuromuscular junctions over periods of several months in living mice. J. Neurosci. 7, 121–1222.

    PubMed  Google Scholar 

  • LOVE, F. M. & THOMPSON, W. J. (1999) Glial cells promote muscle reinnervation by responding to activity-dependent postsynaptic signals. J. Neurosci. 19, 1039–10396.

    PubMed  Google Scholar 

  • LUBISCHER, J. L. & THOMPSON, W. J. (1999) Neonatal partial denervation results in nodal but not terminal sprouting and a decrease in efficacy of remaining neuromuscular junctions in rat soleus muscle. J. Neurosci. 19, 893–8944.

    PubMed  Google Scholar 

  • MACLEOD, G. T., DICKENS, P. A. & BENNETT, M. R. (2001) Formation and function of synapses with respect to Schwann cells at the end of motor nerve terminal branches on mature amphibian (Bufo marinus) muscle. J. Neurosci. 21, 238–2392.

    PubMed  Google Scholar 

  • MILEDI, R. & SLATER, C. R. (1968) Electrophysiology and electron-microscopy of rat neuromuscular junctions after nerve degeneration. Proc. Roy. Soc. Lond. B. 169, 28– 306.

    Google Scholar 

  • MILEDI, R. & SLATER, C. R. (1970) On the degeneration of rat neuromuscular junctions after nerve section. J. Physiol. 207, 50–528.

    PubMed  Google Scholar 

  • MORRIS, J. K., LIN, W., HAUSER, C., MARCHUK, Y., GETMAN, D. & LEE, K. F. (1999) Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development. Neuron 23, 27–283.

    PubMed  Google Scholar 

  • NEWMAN, E. A. (1984) Regional specialization of retinal glial cell membrane. Nature 309, 15–157.

    PubMed  Google Scholar 

  • NGUYEN, Q. T., SANES, J. R. & LICHTMAN, J. W. (2002) Pre-existing pathways promote precise projection patterns. Nat. Neurosci. 5, 86–867.

    PubMed  Google Scholar 

  • O'MALLEY, J. P., WARAN, M. T. & BALICE-GORDON, R. J. (1999) In vivo observations of terminal Schwann cells at normal, denervated, and reinnervated mouse neuromuscular junctions. J. Neurobiol. 38, 27–286.

    PubMed  Google Scholar 

  • PALADE, G. E. (1954) Electron microscope observations of interneuronal and neuromuscular synapses. Anat. Rec. 118, 33–336.

    Google Scholar 

  • PENG, H. B., YANG, J. F., DAI, Z., LEE, C. W., HUNG, H. W., FENG, Z. H. & KO, C. P. (2003) Differential effects of neurotrophins and Schwann cell-derived signals on neuronal survival/growth and synaptogenesis. J. Neurosci. 23, 505–5060.

    PubMed  Google Scholar 

  • PETERS, A. & MUIR, A. R. (1959) The relationship between axons and Schwann cells during development of peripheral nerves in the rat. J. Exp. Physiol. 44, 11–130.

    Google Scholar 

  • RAMON Y CAJAL, S. (1928) Degeneration and Regeneration of the Nervous System. New York: Hafner, translated by R. M., 1959.

    Google Scholar 

  • RANVIER, L. (1878) Le¸cons Sur l'histologies du Syst´eme Nerveux. Volume 2, Paris: Savy.

    Google Scholar 

  • REIST, N. E. & SMITH, S. J. (1992) Neurally evoked calcium transients in terminal Schwann cells at the neuromuscular junction. Proc. Natl. Acad. Sci. USA 89, 762– 7629.

    PubMed  Google Scholar 

  • REYNOLDS, M. L. & WOOLF, C. J. (1992) Terminal Schwann cells elaborate extensive processes following denervation of the motor endplate. J. Neurocytol. 21, 5–66.

    PubMed  Google Scholar 

  • RICH, M. M. & LICHTMAN, J. W. (1989) In vivo visualization of pre-and postsynaptic changes during synapse elimination in reinnervated mouse muscle. J. Neurosci. 9, 178–1805.

    PubMed  Google Scholar 

  • RIETHMACHER, D., SONNENBERG-RIETHMACHER, E., BRINKMAN, V., YAMAAI, T., LEWIN, G. R. & BIRCHMEIER, C. (1997) Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389, 72–730.

    PubMed  Google Scholar 

  • ROBERTSON, J. D. (1956) The ultrastructure of a reptilian myoneural junction. J. Biophys. Biochem. Cytol. 2, 38–394.

    PubMed  Google Scholar 

  • ROBITAILLE, R. (1995) Purinergic receptors and their activation by endogenous purines at perisynaptic glial cells of the frog neuromuscular junction. J. Neurosci. 15, 712–7131.

    PubMed  Google Scholar 

  • ROBITAILLE, R. (1998) Modulation of synaptic efficacy and synaptic depression by glial cells at the frog neuromuscular junction. Neuron 21, 84–855.

    PubMed  Google Scholar 

  • ROCHEL, S. & ROBBINS, N. (1988) Effect of partial denervation and terminal field expansion on neuromuscular transmitter release and nerve terminal structure. J. Neurosci. 8, 33–338.

    PubMed  Google Scholar 

  • ROCHON, D., ROUSSE, I. & ROBITAILLE, R. (2001) Synapse-glia interactions at the mammalian neuromuscular junction. J. Neurosci. 21, 381–3829.

    PubMed  Google Scholar 

  • SCHERER, S. S. & SALZER, J. L. (1996) Axon-Schwann cell interactions during peripheral nerve degeneration and regeneration. In Glial Cell Development (edited by JESSEN, K. R. & RICHARDSON, W. D.) pp. 16–196. Oxford: BIOS Scientific Publishers.

    Google Scholar 

  • SCHWANN, T. (1839) Microscopical Researches Into the Accordance in the Structure and Growth of Animals and Plants. London: Sydenham Society.

    Google Scholar 

  • SLACK, J. R. & HOPKINS, W. G. (1982) Neuromuscular transmission at terminals of sprouted mammalian motor neurones. Brain Res. 237, 12–135.

    PubMed  Google Scholar 

  • SON, Y.-J. & THOMPSON, W. J. (1995a) Schwann cell processes guide regeneration of peripheral axons. Neuron 14, 12–132.

    PubMed  Google Scholar 

  • SON, Y.-J. & THOMPSON, W. J. (1995b) Nerve sprouting in muscle is induced and guided by processes extended by Schwann cells. Neuron 14, 13–141.

    PubMed  Google Scholar 

  • SPEIDEL, C. C. (1932) Studies of living nerves. I. The movements of individual sheath cells and nerve sprouts correlated with the process of myelin-sheath formation in amphibian larvae. J. Exp. Zool. 61, 27–331.

    Google Scholar 

  • TELLO, F. (1907) Degeneration et regeneration des plagues motrices. Travaux du Laboratorire de Recherches Biologiques de l'Universit'e de Madrid 5, 11–149.

    Google Scholar 

  • THOMPSON, W. (1978) Reinnervation of partially denervated rat soleus muscle. Acta Physiol. Scand. 103, 8–91.

    PubMed  Google Scholar 

  • TIAN, L. & THOMPSON, W. J. (2000) Neuromuscular synaptic instability is produced by long-term partial denervation in adult rat muscles. Soc. Neurosci. Abs. 26, 703.3.

    Google Scholar 

  • TIAN, L. & THOMPSON, W. J. (2002) Schwann cells induce and guide nerve growth during sprouting in reinnervated soleus muscles in vivo. Soc. Neurosci. Abs. 28, 234.14.

    Google Scholar 

  • TRACHTENBERG, J. T. & THOMPSON, W. J. (1996) Schwann cell apoptosis at developing neuromuscular junctions is regulated by glial growth factor. Nature 379, 17–177.

    PubMed  Google Scholar 

  • TRACHTENBERG, J. T. & THOMPSON, W. J. (1997) Nerve terminal withdrawal from rat neuromuscular junctions induced by neuregulin and Schwann cells. J. Neurosci. 17, 624–6255.

    PubMed  Google Scholar 

  • VERDI, J. M., GROVES, A. K., FARIÑAS, I., JONES, K., MARCHIONNI, M. A., REICHARDT, L. F. & ANDERSON, D. J. (1996) A reciprocal cell-cell interaction mediated by NT-3 and neuregulins controls the early survival and development of sympathetic neuroblasts. Neuron 16, 51–527.

    PubMed  Google Scholar 

  • WALSH, M. K. & LICHTMAN, J. W. (2003) In vivo timelapse imaging of synaptic takeover associated with naturally occurring synapse elimination. Neuron 37, 6– 73.

    PubMed  Google Scholar 

  • WOLPOWITZ, D., MASON, T. B., DIETRICH, P., MENDELSOHN, M., TALMAGE, D. A. & ROLE, L. W. (2000) Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses. Neuron 25, 7–91.

    PubMed  Google Scholar 

  • YOUNG, J. Z. (1942) The functional repair of nervous tissue. Physiol. Rev. 22, 31–374.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kang, H., Tian, L. & Thompson, W. Terminal Schwann cells guide the reinnervation of muscle after nerve injury. J Neurocytol 32, 975–985 (2003). https://doi.org/10.1023/B:NEUR.0000020636.27222.2d

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:NEUR.0000020636.27222.2d

Keywords

Navigation