iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://doi.org/10.1007/s00441-006-0237-x
Development of the neuromuscular junction | Cell and Tissue Research Skip to main content
Springer Nature Link
Log in

Development of the neuromuscular junction

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

The differentiation of the neuromuscular junction is a multistep process requiring coordinated interactions between nerve terminals and muscle. Although innervation is not needed for muscle production, the formation of nerve-muscle contacts, intramuscular nerve branching, and neuronal survival require reciprocal signals from nerve and muscle to regulate the formation of synapses. Following the production of muscle fibers, clusters of acetylcholine receptors (AChRs) are concentrated in the central regions of the myofibers via a process termed “prepatterning”. The postsynaptic protein MuSK is essential for this process activating possibly its own expression, in addition to the expression of AChR. AChR complexes (aggregated and stabilized by rapsyn) are thus prepatterned independently of neuronal signals in developing myofibers. ACh released by branching motor nerves causes AChR-induced postsynaptic potentials and positively regulates the localization and stabilization of developing synaptic contacts. These “active” contact sites may prevent AChRs clustering in non-contacted regions and counteract the establishment of additional contacts. ACh-induced signals also cause the dispersion of non-synaptic AChR clusters and possibly the removal of excess AChR. A further neuronal factor, agrin, stabilizes the accumulation of AChR at synaptic sites. Agrin released from the branching motor nerve may form a structural link specifically to the ACh-activated endplates, thereby enhancing MuSK kinase activity and AChR accumulation and preventing dispersion of postsynaptic specializations. The successful stabilization of prepatterned AChR clusters by agrin and the generation of singly innervated myofibers appear to require AChR-mediated postsynaptic potentials indicating that the differentiation of the nerve terminal proceeds only after postsynaptic specializations have formed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Arber S, Han B, Mendelsohn M, Smith M, Jessell TM, Sockanathan S (1999) Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity. Neuron 23:659–674

    Article  PubMed  CAS  Google Scholar 

  • Arber S, Burden SJ, Harris AJ (2002) Patterning of skeletal muscle. Curr Opin Neurobiol 12:100–103

    Article  PubMed  CAS  Google Scholar 

  • Banks GB, Chau TN, Bartlett SE, Noakes PG (2001) Promotion of motoneuron survival and branching in rapsyn-deficient mice. J Comp Neurol 429:156–165

    Article  PubMed  CAS  Google Scholar 

  • Brandon EP, Lin W, D’Amour KA, Pizzo DP, Dominguez B, Sugiura Y, Thode S, Ko CP, Thal LJ, Gage FH, Lee KF (2003) Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. J Neurosci 23:539–549

    PubMed  CAS  Google Scholar 

  • Brenner HR, Witzemann V, Sakmann B (1990) Imprinting of acetylcholine receptor messenger RNA accumulation in mammalian neuromuscular synapses. Nature 344:544–547

    Article  PubMed  CAS  Google Scholar 

  • Buckingham M, Bajard L, Chang T, Daubas P, Hadchouel J, Meilhac S, Montarras D, Rocancourt D, Relaix F (2003) The formation of skeletal muscle: from somite to limb. J Anat 202:59–68

    Article  PubMed  Google Scholar 

  • Buffelli M, Burgess RW, Feng G, Lobe CG, Lichtman JW, Sanes JR (2003) Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition. Nature 424:430–434

    Article  PubMed  CAS  Google Scholar 

  • Buonanno A, Fischbach GD (2001) Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol 11:287–296

    Article  PubMed  CAS  Google Scholar 

  • Burden SJ, Sargent PB, McMahan UJ (1979) Acetylcholine receptors in regenerating muscle accumulate at original synaptic sites in the absence of the nerve. J Cell Biol 82:412–425

    Article  PubMed  CAS  Google Scholar 

  • Campagna JA, Ruegg MA, Bixby JL (1995) Agrin is a differentiation-inducing “stop signal” for motoneurons in vitro. Neuron 15:1365–1374

    Article  PubMed  CAS  Google Scholar 

  • Christ B, Brand-Saberi B (2002) Limb muscle development. Int J Dev Biol 46:905–914

    PubMed  CAS  Google Scholar 

  • Colquhoun D, Sakmann B (1998) From muscle endplate to brain synapses: a short history of synapses and agonist-activated ion channels. Neuron 20:381–387

    Article  PubMed  CAS  Google Scholar 

  • Couteaux R (1973) Motor endplate structure. In: Bourne GH (ed) Structure and function of muscle, vol 2. Academic Press, New York, pp 483–530

    Google Scholar 

  • DeChiara TM, Bowen DC, Valenzuela DM, Simmons MV, Poueymirou WT, Thomas S, Kinetz E, Compton DL, Rojas E, Park JS, Smith C, DiStefano PS, Glass DJ, Burden SJ, Yancopoulos GD (1996) The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell 85:501–512

    Article  PubMed  CAS  Google Scholar 

  • Dimitropoulou A, Bixby JL (2005) Motor neurite outgrowth is selectively inhibited by cell surface MuSK and agrin. Mol Cell Neurosci 28:292–302

    Article  PubMed  CAS  Google Scholar 

  • Duclert A, Changeux JP (1995) Acetylcholine receptor gene expression at the developing neuromuscular junction. Physiol Rev 75:339–368

    PubMed  CAS  Google Scholar 

  • Escher P, Lacazette E, Courtet M, Blindenbacher A, Landmann L, Bezakova G, Lloyd KC, Mueller U, Brenner HR (2005) Synapses form in skeletal muscles lacking neuregulin receptors. Science 308:1920–1923

    Article  PubMed  CAS  Google Scholar 

  • Esper RM, Pankonin MS, Loeb JA (2006) Neuregulins: versatile growth and differentiation factors in nervous system development and human disease. Brain Res Brain Res Rev (Epub ahead of print)

  • Falls DL, Rosen KM, Corfas G, Lane WS, Fischbach GD (1993) ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell 72:801–815

    Article  PubMed  CAS  Google Scholar 

  • Froehner SC (1993) Regulation of ion channel distribution at synapses. Annu Rev Neurosci 16:347–368

    Article  PubMed  CAS  Google Scholar 

  • Garratt AN, Britsch S, Birchmeier C (2000) Neuregulin, a factor with many functions in the life of a Schwann cell. Bioessays 22:987–996

    Article  PubMed  CAS  Google Scholar 

  • Gassmann M, Casagranda F, Orioli D, Simon H, Lai C, Klein R, Lemke G (1995) Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378:390–394

    Article  PubMed  CAS  Google Scholar 

  • Gautam M, Noakes PG, Mudd J, Nichol M, Chu GC, Sanes JR, Merlie JP (1995) Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice. Nature 377:232–236

    Article  PubMed  CAS  Google Scholar 

  • Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP, Sanes JR (1996) Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell 85:525–535

    Article  PubMed  CAS  Google Scholar 

  • Gesemann M, Denzer AJ, Ruegg MA (1995) Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site. J Cell Biol 128:625–636

    Article  PubMed  CAS  Google Scholar 

  • Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD (1996) Agrin acts via a MuSK receptor complex. Cell 85:513–523

    Article  PubMed  CAS  Google Scholar 

  • Grady RM, Starr DA, Ackerman GL, Sanes JR, Han M (2005) Syne proteins anchor muscle nuclei at the neuromuscular junction. Proc Natl Acad Sci USA 102:4359–4364

    Article  PubMed  CAS  Google Scholar 

  • Greer JJ, Allan DW, Martin-Caraballo M, Lemke RP (1999) An overview of phrenic nerve and diaphragm muscle development in the perinatal rat. J Appl Physiol 86:779–786

    Article  PubMed  CAS  Google Scholar 

  • Heeroma JH, Plomp JJ, Roubos EW, Verhage M (2003) Development of the mouse neuromuscular junction in the absence of regulated secretion. Neuroscience 120:733–744

    Article  PubMed  CAS  Google Scholar 

  • Herbst R, Burden SJ (2000) The juxtamembrane region of MuSK has a critical role in agrin-mediated signaling. EMBO J 19:67–77

    Article  PubMed  CAS  Google Scholar 

  • Hesser BA, Sander A, Witzemann V (1999) Identification and characterization of a novel splice variant of MuSK. FEBS Lett 442:133–137

    Article  PubMed  CAS  Google Scholar 

  • Hesser BA, Henschel O, Witzemann V (2006) Synapse disassembly and formation of new synapses in postnatal muscle upon conditional inactivation of MuSK. Mol Cell Neurosci 31:470–480

    Article  PubMed  CAS  Google Scholar 

  • Hughes DS, Schade RR, Ontell M (1992) Ablation of the fetal mouse spinal cord: the effect on soleus muscle cytoarchitecture. Dev Dyn 193:164–174

    PubMed  CAS  Google Scholar 

  • Jaworski A, Burden SJ (2006) Neuromuscular synapse formation in mice lacking motor neuron- and skeletal muscle-derived neuregulin-1. J Neurosci 26:655–661

    Article  PubMed  CAS  Google Scholar 

  • Jennings CG, Dyer SM, Burden SJ (1993) Muscle-specific trk-related receptor with a kringle domain defines a distinct class of receptor tyrosine kinases. Proc Natl Acad Sci USA 90:2895–2899

    Article  PubMed  CAS  Google Scholar 

  • Jones G, Moore C, Hashemolhosseini S, Brenner HR (1999) Constitutively active MuSK is clustered in the absence of agrin and induces ectopic postsynaptic-like membranes in skeletal muscle fibers. J Neurosci 19:3376–3383

    PubMed  CAS  Google Scholar 

  • Kablar B, Rudnicki MA (1999) Development in the absence of skeletal muscle results in the sequential ablation of motor neurons from the spinal cord to the brain. Dev Biol 208:93–109

    Article  PubMed  CAS  Google Scholar 

  • Koenen M, Peter C, Villarroel A, Witzemann V, Sakmann B (2005) Acetylcholine receptor channel subtype directs the innervation pattern of skeletal muscle. EMBO Rep 6:570–576

    Article  PubMed  CAS  Google Scholar 

  • Kong XC, Barzaghi P, Ruegg MA (2004) Inhibition of synapse assembly in mammalian muscle in vivo by RNA interference. EMBO Rep 5:183–188

    Article  PubMed  CAS  Google Scholar 

  • Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378:394–398

    Article  PubMed  CAS  Google Scholar 

  • Lin W, Burgess RW, Dominguez B, Pfaff SL, Sanes JR, Lee KF (2001) Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 410:1057–1064

    Article  PubMed  CAS  Google Scholar 

  • Lin W, Dominguez B, Yang J, Aryal P, Brandon EP, Gage FH, Lee KF (2005) Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism. Neuron 46:569–579

    Article  PubMed  CAS  Google Scholar 

  • Luo ZG, Wang Q, Zhou JZ, Wang J, Luo Z, Liu M, He X, Wynshaw-Boris A, Xiong WC, Lu B, Mei L (2002) Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1. Neuron 35:489–505

    Article  PubMed  CAS  Google Scholar 

  • Luo ZG, Je HS, Wang Q, Yang F, Dobbins GC, Yang ZH, Xiong WC, Lu B, Mei L (2003) Implication of geranylgeranyltransferase I in synapse formation. Neuron 40:703–717

    Article  PubMed  CAS  Google Scholar 

  • McMahan UJ (1990) The agrin hypothesis. Cold Spring Harb Symp Quant Biol 55:407–418

    PubMed  CAS  Google Scholar 

  • Meyer D, Birchmeier C (1995) Multiple essential functions of neuregulin in development. Nature 378:386–390

    Article  PubMed  CAS  Google Scholar 

  • Misgeld T, Burgess RW, Lewis RM, Cunningham JM, Lichtman JW, Sanes JR (2002) Roles of neurotransmitter in synapse formation: development of neuromuscular junctions lacking choline acetyltransferase. Neuron 36:635–648

    Article  PubMed  CAS  Google Scholar 

  • Misgeld T, Kummer TT, Lichtman JW, Sanes JR (2005) Agrin promotes synaptic differentiation by counteracting an inhibitory effect of neurotransmitter. Proc Natl Acad Sci USA 102:11088–11093

    Article  PubMed  CAS  Google Scholar 

  • Mishina M, Takai T, Imoto K, Noda M, Takahashi T, Numa S, Methfessel C, Sakmann B (1986) Molecular distinction between fetal and adult forms of muscle acetylcholine receptor. Nature 321:406–411

    Article  PubMed  CAS  Google Scholar 

  • Missias AC, Mudd J, Cunningham JM, Steinbach JH, Merlie JP, Sanes JR (1997) Deficient development and maintenance of postsynaptic specializations in mutant mice lacking an “adult” acetylcholine receptor subunit. Development 124:5075–5086

    PubMed  CAS  Google Scholar 

  • Morris JK, Lin W, Hauser C, Marchuk Y, Getman D, Lee KF (1999) Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development. Neuron 23:273–283

    Article  PubMed  CAS  Google Scholar 

  • Musil LS, Frail DE, Merlie JP (1989) The mammalian 43-kD acetylcholine receptor-associated protein (RAPsyn) is expressed in some nonmuscle cells. J Cell Biol 108:1833–1840

    Article  PubMed  CAS  Google Scholar 

  • Neubig RR, Krodel EK, Boyd ND, Cohen JB (1979) Acetylcholine and local anesthetic binding to Torpedo nicotinic postsynaptic membranes after removal of nonreceptor peptides. Proc Natl Acad Sci USA 76:690–694

    Article  PubMed  CAS  Google Scholar 

  • Nikovits W Jr, Cann GM, Huang R, Christ B, Stockdale FE (2001) Patterning of fast and slow fibers within embryonic muscles is established independently of signals from the surrounding mesenchyme. Development 128:2537–2544

    PubMed  CAS  Google Scholar 

  • Numberger M, Durr I, Kues W, Koenen M, Witzemann V (1991) Different mechanisms regulate muscle-specific AChR gamma- and epsilon-subunit gene expression. EMBO J 10:2957–2964

    PubMed  CAS  Google Scholar 

  • Ontell M, Kozeka K (1984) Organogenesis of the mouse extensor digitorum logus muscle: a quantitative study. Am J Anat 171:149–161

    Article  PubMed  CAS  Google Scholar 

  • Relaix F, Rocancourt D, Mansouri A, Buckingham M (2005) A Pax3/Pax7-dependent population of skeletal muscle progenitor cells. Nature 435:948–953

    Article  PubMed  CAS  Google Scholar 

  • Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C (1997) Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389:725–730

    Article  PubMed  CAS  Google Scholar 

  • Rizo J, Sudhof TC (2002) Snares and Munc18 in synaptic vesicle fusion. Nat Rev Neurosci 3:641–653

    PubMed  CAS  Google Scholar 

  • Ross JJ, Duxson MJ, Harris AJ (1987) Formation of primary and secondary myotubes in rat lumbrical muscles. Development 100:383–394

    PubMed  CAS  Google Scholar 

  • Sakmann B, Brenner HR (1978) Change in synaptic channel gating during neuromuscular development. Nature 276:401–402

    Article  PubMed  CAS  Google Scholar 

  • Sander A, Hesser BA, Witzemann V (2001) MuSK induces in vivo acetylcholine receptor clusters in a ligand-independent manner. J Cell Biol 155:1287–1296

    Article  PubMed  CAS  Google Scholar 

  • Sanes JR, Lichtman JW (2001) Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Rev Neurosci 2:791–805

    Article  PubMed  CAS  Google Scholar 

  • Sanes JR, Marshall LM, McMahan UJ (1978) Reinnervation of muscle fiber basal lamina after removal of myofibers. Differentiation of regenerating axons at original synaptic sites. J Cell Biol 78:176–198

    Article  PubMed  CAS  Google Scholar 

  • Schaeffer L, Kerchove d’Exaerde A de, Changeux JP (2001) Targeting transcription to the neuromuscular synapse. Neuron 31:15–22

    Article  PubMed  CAS  Google Scholar 

  • Sobel A, Weber M, Changeux JP (1977) Large-scale purification of the acetylcholine-receptor protein in its membrane-bound and detergent-extracted forms from Torpedo marmorata electric organ. Eur J Biochem 80:215–224

    Article  PubMed  CAS  Google Scholar 

  • Takahashi M, Kubo T, Mizoguchi A, Carlson CG, Endo K, Ohnishi K (2002) Spontaneous muscle action potentials fail to develop without fetal-type acetylcholine receptors. EMBO Rep 3:674–681

    Article  PubMed  CAS  Google Scholar 

  • Terrado J, Burgess RW, DeChiara T, Yancopoulos G, Sanes JR, Kato AC (2001) Motoneuron survival is enhanced in the absence of neuromuscular junction formation in embryos. J Neurosci 21:3144–3150

    PubMed  CAS  Google Scholar 

  • Thaler J, Harrison K, Sharma K, Lettieri K, Kehrl J, Pfaff SL (1999) Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9. Neuron 23:675–687

    Article  PubMed  CAS  Google Scholar 

  • Valenzuela DM, Stitt TN, DiStefano PS, Rojas E, Mattsson K, Compton DL, Nunez L, Park JS, Stark JL, Gies DR et al (1995) Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. Neuron 15:573–584

    Article  PubMed  CAS  Google Scholar 

  • Verhage M, Maia AS, Plomp JJ, Brussaard AB, Heeroma JH, Vermeer H, Toonen RF, Hammer RE, Berg TK van den, Missler M, Geuze HJ, Sudhof TC (2000) Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287:864–869

    Article  PubMed  CAS  Google Scholar 

  • Weston C, Yee B, Hod E, Prives J (2000) Agrin-induced acetylcholine receptor clustering is mediated by the small guanosine triphosphatases Rac and Cdc42. J Cell Biol 150:205–212

    Article  PubMed  CAS  Google Scholar 

  • Witzemann V, Barg B, Criado M, Stein E, Sakmann B (1989) Developmental regulation of five subunit specific mRNAs encoding acetylcholine receptor subtypes in rat muscle. FEBS Lett 242:419–424

    Article  PubMed  CAS  Google Scholar 

  • Witzemann V, Schwarz H, Koenen M, Berberich C, Villarroel A, Wernig A, Brenner HR, Sakmann B (1996) Acetylcholine receptor epsilon-subunit deletion causes muscle weakness and atrophy in juvenile and adult mice. Proc Natl Acad Sci USA 93:13286–13291

    Article  PubMed  CAS  Google Scholar 

  • Woldeyesus MT, Britsch S, Riethmacher D, Xu L, Sonnenberg-Riethmacher E, Abou-Rebyeh F, Harvey R, Caroni P, Birchmeier C (1999) Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development. Genes Dev 13:2538–2548

    Article  PubMed  CAS  Google Scholar 

  • Yang X, Li W, Prescott ED, Burden SJ, Wang JC (2000) DNA topoisomerase IIbeta and neural development. Science 287:131–134

    Article  PubMed  CAS  Google Scholar 

  • Yang X, Arber S, William C, Li L, Tanabe Y, Jessell TM, Birchmeier C, Burden SJ (2001) Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation. Neuron 30:399–410

    Article  PubMed  CAS  Google Scholar 

  • Young SH, Poo MM (1983) Spontaneous release of transmitter from growth cones of embryonic neurones. Nature 305:634–637

    Article  PubMed  CAS  Google Scholar 

  • Zhou H, Glass DJ, Yancopoulos GD, Sanes JR (1999) Distinct domains of MuSK mediate its abilities to induce and to associate with postsynaptic specializations. J Cell Biol 146:1133–1146

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

I thank Dr. D.J. Haydon-Wallace for critically reading the manuscript. I also thank Drs. M. Koenen and F. Chevessier for discussions and U. Mersdorf for technical assistance.

Author information

Authors and Affiliations

  1. Max-Planck-Institut fur medizinische Forschung, Jahnstrasse 29, 69120, Heidelberg, Germany

    Veit Witzemann

Authors
  1. Veit Witzemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Veit Witzemann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Witzemann, V. Development of the neuromuscular junction. Cell Tissue Res 326, 263–271 (2006). https://doi.org/10.1007/s00441-006-0237-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-006-0237-x

Keywords

Search

Navigation