Cell Adhesion Molecules at the Drosophila Neuromuscular Junction

  • Franklin A. Carrero-MartínezEmail author
  • Akira Chiba


A major goal in neuroscience is the understanding of organizational principles underlying cellular communication and the ensuing molecular integrations that lead to a functional nervous system. The establishment of neuromuscular connections (junctions) is a complex process that requires enumerable cellular and molecular interactions. There are many known and well-characterized molecular events involved in every aspect of neuromuscular junction (NMJ) formation. For instance, at the presynaptic side the motoneuron must differentiate, polarize, undergo dendrogenesis and axogenesis, and extend its processes out to the muscle field. This requires axon guidance, pathfinding, and finally synaptogenesis. At the postsynaptic side, the muscle cell must differentiate and find its correct place in the embryonic body plan to receive motor axons. There are many molecules known to play essential roles during each step in these self-organizational processes. Genetic and biochemical studies have identified molecules that facilitate accurate synaptic target recognitions, as well as those responsible for pre- and postsynaptic specializations. Cell adhesion molecules (CAMs) are known to play an essential role in establishing the NMJ. In this chapter, we begin by exploring Drosophila and its NMJ as a model system for glutamatergic synapses in the mammalian central nervous system. We continue by discussing selected CAMs, with known roles in Drosophila NMJ formation. We also explore the role these CAMs play in establishing the basic cytoarchitecture that ultimately results in functional neuromuscular synapses. We then examine the role CAMs play in synapse formation and plasticity. We conclude by providing an integrative model for CAMs function during synapse formation.


Drosophila Filopodia Myopodia Cell adhesion molecule (CAM) Capricious (Caps) Connectin (Con) Down syndrome cell adhesion molecule (Dscam) Fasciclin II (FasII) Fasciclin III (FasIII) Integrin N-Cadherin Neuroglian (Nrg) Toll 



We thank Dr. Julie Dutil and Grissell Carrero-Martínez for editorial comments and suggestions on the manuscript. We also thank Dr. O’Neil Guthrie for helpful scientific discussions and comments and Dr. Daniel P. Kiehart for access to valuable resources and critical comments. F.A.C.-M. is an ASCB MAC visiting scholar with D.P.K. This award is supported by a MARC grant from the NIH NIGMS to the American Society for Cell Biology Minorities Affairs Committee.


  1. Abrell S and Jackle H (2001) Axon guidance of Drosophila SNb motoneurons depends on the cooperative action of muscular Kruppel and neuronal capricious activities. Mech Dev 109:3–12CrossRefPubMedGoogle Scholar
  2. Ackley BD, Kang SH, Crew JR et al. (2003) The basement membrane components nidogen and Type XVIII collagen regulate organization of neuromuscular junctions in Caenorhabditis elegans. J Neurosci 23:3577–3587PubMedGoogle Scholar
  3. Adams MD, Celniker SE, Holt RA et al. (2000) The genome sequence of Drosophila melanogaster. Science 287:2185–2195CrossRefPubMedGoogle Scholar
  4. Ashley J, Packard M, Ataman B et al. (2005) Fasciclin II signals new synapse formation through amyloid precursor protein and the scaffolding protein dX11/Mint. J Neurosci 25:5943–5955CrossRefPubMedGoogle Scholar
  5. Bate M and Rushton E (1993) Myogenesis and muscle patterning in Drosophila. C R Acad Sci III 316:1047–1061PubMedGoogle Scholar
  6. Beumer K, Matthies HJ, Bradshaw A et al. (2002) Integrins regulate DLG/FAS2 via a CaM kinase II-dependent pathway to mediate synapse elaboration and stabilization during postembryonic development. Development 129:3381–3391PubMedGoogle Scholar
  7. Beumer KJ, Rohrbough J, Prokop A et al. (1999) A role for PS integrins in morphological growth and synaptic function at the postembryonic neuromuscular junction of Drosophila. Development 126:5833–5846PubMedGoogle Scholar
  8. Bieber AJ, Snow PM, Hortsch M et al. (1989) Drosophila neuroglian: a member of the immunoglobulin superfamily with extensive homology to the vertebrate neural adhesion molecule L1. Cell 59:447–460CrossRefPubMedGoogle Scholar
  9. Bloor JW and Brown NH (1998) Genetic analysis of the Drosophila alphaPS2 integrin subunit reveals discrete adhesive, morphogenetic and sarcomeric functions. Genetics 148:1127–1142PubMedGoogle Scholar
  10. Bloor JW and Kiehart DP (2001) zipper Nonmuscle Myosin-II functions downstream of PS2 integrin in Drosophila myogenesis and is necessary for myofibril formation. Dev Biol 239:215–228CrossRefPubMedGoogle Scholar
  11. Bokel C and Brown NH (2002) Integrins in development: moving on, responding to, and sticking to the extracellular matrix. Dev Cell 3:311–321CrossRefPubMedGoogle Scholar
  12. Bouley M, Tian MZ, Paisley K et al. (2000) The L1-type cell adhesion molecule neuroglian influences the stability of neural ankyrin in the Drosophila embryo but not its axonal localization. J Neurosci 20:4515–4523PubMedGoogle Scholar
  13. Broadie K and Bate M (1993) Muscle development is independent of innervation during Drosophila embryogenesis. Development 119:533–543PubMedGoogle Scholar
  14. Brown NH (2000) Cell-cell adhesion via the ECM: integrin genetics in fly and worm. Matrix Biol 19:191–201CrossRefPubMedGoogle Scholar
  15. Budnik V (1996) Synapse maturation and structural plasticity at Drosophila neuromuscular junctions. Curr Opin Neurobiol 6:858–867CrossRefPubMedGoogle Scholar
  16. Campos-Ortega JA and Hartenstein V (1985) The Embryonic Development of Drosophila melanogaster. Springer-Verlag, Berlin, New YorkGoogle Scholar
  17. Cash S, Chiba A and Keshishian H (1992) Alternate neuromuscular target selection following the loss of single muscle fibers in Drosophila. J Neurosci 12:2051–2064PubMedGoogle Scholar
  18. Cheng Y, Endo K, Wu K et al. (2001) Drosophila fasciclinII is required for the formation of odor memories and for normal sensitivity to alcohol. Cell 105:757–768CrossRefPubMedGoogle Scholar
  19. Chiba A (1999) Early development of the Drosophila neuromuscular junction: a model for studying neuronal networks in development. Int Rev Neurobiol 43:1–24CrossRefPubMedGoogle Scholar
  20. Chiba A, Snow P, Keshishian H et al. (1995) Fasciclin III as a synaptic target recognition molecule in Drosophila. Nature 374:166–168CrossRefPubMedGoogle Scholar
  21. Crossley CA (1978) The morphology and development of the Drosophila muscular system. In: Ashburner M and Wright TRF (eds) The Genetics and Biology of Drosophila. Academic Press, New YorkGoogle Scholar
  22. Currie DA and Bate M (1991) The development of adult abdominal muscles in Drosophila: myoblasts express twist and are associated with nerves. Development 113:91–102PubMedGoogle Scholar
  23. Currie DA and Bate M (1995) Innervation is essential for the development and differentiation of a sex-specific adult muscle in Drosophila melanogaster. Development 121:2549–2557PubMedGoogle Scholar
  24. Davis GW and Goodman CS (1998) Genetic analysis of synaptic development and plasticity: homeostatic regulation of synaptic efficacy. Curr Opin Neurobiol 8:149–156CrossRefPubMedGoogle Scholar
  25. Davis GW, Schuster CM and Goodman CS (1997) Genetic analysis of the mechanisms controlling target selection: target-derived Fasciclin II regulates the pattern of synapse formation. Neuron 19:561–573CrossRefPubMedGoogle Scholar
  26. Dworak HA and Sink H (2002) Myoblast fusion in Drosophila. Bioessays 24:591–601CrossRefPubMedGoogle Scholar
  27. Featherstone DE, Davis WS, Dubreuil RR et al. (2001) Drosophila alpha- and beta-spectrin mutations disrupt presynaptic neurotransmitter release. J Neurosci 21:4215–4224PubMedGoogle Scholar
  28. Fessler JH and Fessler LI (1989) Drosophila extracellular matrix. Annu Rev Cell Biol 5:309–339CrossRefPubMedGoogle Scholar
  29. Gotwals PJ, Fessler LI, Wehrli M et al. (1994) Drosophila PS1 integrin is a laminin receptor and differs in ligand specificity from PS2. Proc Natl Acad Sci USA 91:11447–11451CrossRefPubMedGoogle Scholar
  30. Grenningloh G, Rehm EJ and Goodman CS (1991) Genetic analysis of growth cone guidance in Drosophila: fasciclin II functions as a neuronal recognition molecule. Cell 67:45–57CrossRefPubMedGoogle Scholar
  31. Grotewiel MS, Beck CD, Wu KH et al. (1998) Integrin-mediated short-term memory in Drosophila. Nature 391:455–460CrossRefPubMedGoogle Scholar
  32. Halbleib JM and Nelson WJ (2006) Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev 20:3199–3214CrossRefPubMedGoogle Scholar
  33. Hall SG and Bieber AJ (1997) Mutations in the Drosophila neuroglian cell adhesion molecule affect motor neuron pathfinding and peripheral nervous system patterning. J Neurobiol 32:325–340CrossRefPubMedGoogle Scholar
  34. Hartenstein V (1993) Atlas of Drosophila development. Cold Spring Harbor Laboratory Press, Plainview, NYGoogle Scholar
  35. Hebbar S, Hall RE, Demski SA et al. (2006) The adult abdominal neuromuscular junction of Drosophila: a model for synaptic plasticity. J Neurobiol 66:1140–1155CrossRefPubMedGoogle Scholar
  36. Hoang B and Chiba A (1998) Genetic analysis on the role of integrin during axon guidance in Drosophila. J Neurosci 18:7847–7855PubMedGoogle Scholar
  37. Hoang B and Chiba A (2001) Single-cell analysis of Drosophila larval neuromuscular synapses. Dev Biol 229:55–70CrossRefPubMedGoogle Scholar
  38. Hortsch M (2000) Structural and functional evolution of the L1 family: are four adhesion molecules better than one? Mol Cell Neurosci 15:1–10CrossRefPubMedGoogle Scholar
  39. Hortsch M, Bieber AJ, Patel NH et al. (1990) Differential splicing generates a nervous system-specific form of Drosophila neuroglian. Neuron 4:697–709CrossRefPubMedGoogle Scholar
  40. Iwai Y, Usui T, Hirano S et al. (1997) Axon patterning requires DN-cadherin, a novel neuronal adhesion receptor, in the Drosophila embryonic CNS. Neuron 19:77–89CrossRefPubMedGoogle Scholar
  41. Johansen J, Halpern ME and Keshishian H (1989) Axonal guidance and the development of muscle fiber-specific innervation in Drosophila embryos. J Neurosci 9:4318–4332PubMedGoogle Scholar
  42. Keshishian H, Broadie K, Chiba A et al. (1996) The drosophila neuromuscular junction: a model system for studying synaptic development and function. Annu Rev Neurosci 19:545–575CrossRefPubMedGoogle Scholar
  43. Koch I, Schwarz H, Beuchle D et al. (2008) Drosophila Ankyrin 2 is required for synaptic stability. Neuron 58:210–222CrossRefPubMedGoogle Scholar
  44. Kohsaka H, Takasu E and Nose A (2007) In vivo induction of postsynaptic molecular assembly by the cell adhesion molecule Fasciclin2. J Cell Biol 179:1289–1300CrossRefPubMedGoogle Scholar
  45. Landgraf M, Bossing T, Technau GM et al. (1997) The origin, location, and projections of the embryonic abdominal motorneurons of Drosophila. J Neurosci 17:9642–9655PubMedGoogle Scholar
  46. Landgraf M, Jeffrey V, Fujioka M et al. (2003) Embryonic origins of a motor system: motor dendrites form a myotopic map in Drosophila. PLoS Biol 1:E41CrossRefPubMedGoogle Scholar
  47. Lin DM, Fetter RD, Kopczynski C et al. (1994) Genetic analysis of Fasciclin II in Drosophila: defasciculation, refasciculation, and altered fasciculation. Neuron 13:1055–1069CrossRefPubMedGoogle Scholar
  48. Lin DM and Goodman CS (1994) Ectopic and increased expression of Fasciclin II alters motoneuron growth cone guidance. Neuron 13:507–523CrossRefPubMedGoogle Scholar
  49. Llano E, Pendas AM, Aza-Blanc P et al. (2000) Dm1-MMP, a matrix metalloproteinase from Drosophila with a potential role in extracellular matrix remodeling during neural development. J. Biol. Chem. 275:35978–35985CrossRefPubMedGoogle Scholar
  50. Lunstrum GP, Bachinger HP, Fessler LI et al. (1988) Drosophila basement membrane procollagen IV. I. Protein characterization and distribution. J Biol Chem 263:18318–18327PubMedGoogle Scholar
  51. McFarlane S (2003) Metalloproteases: carving out a role in axon guidance. Neuron 37:559–562CrossRefPubMedGoogle Scholar
  52. Miller CM, Page-McCaw A and Broihier HT (2008) Matrix metalloproteinases promote motor axon fasciculation in the Drosophila embryo. Development 135:95–109CrossRefPubMedGoogle Scholar
  53. Mirre C, Cecchini JP, Le Parco Y et al. (1988) De novo expression of a type IV collagen gene in Drosophila embryos is restricted to mesodermal derivatives and occurs at germ band shortening. Development 102:369–376PubMedGoogle Scholar
  54. Misgeld T, Burgess RW, Lewis RM et al. (2002) Roles of neurotransmitter in synapse formation: development of neuromuscular junctions lacking choline acetyltransferase. Neuron 36:635–648CrossRefPubMedGoogle Scholar
  55. Nose A (2008) Personal communication and laboratory website ( 7/20/2008 3:54 PMGoogle Scholar
  56. Nose A, Mahajan VB and Goodman CS (1992) Connectin: a homophilic cell adhesion molecule expressed on a subset of muscles and the motoneurons that innervate them in Drosophila. Cell 70:553–567CrossRefPubMedGoogle Scholar
  57. Nose A, Umeda T and Takeichi M (1997) Neuromuscular target recognition by a homophilic interaction of connectin cell adhesion molecules in Drosophila. Development 124:1433–1441PubMedGoogle Scholar
  58. Packard M, Mathew D and Budnik V (2003) FASt remodeling of synapses in Drosophila. Curr Opin Neurobiol 13:527–534CrossRefPubMedGoogle Scholar
  59. Page-McCaw A (2008) Remodeling the model organism: matrix metalloproteinase functions in invertebrates. Semin Cell Dev Biol 19:14–23CrossRefPubMedGoogle Scholar
  60. Rivlin PK, Ryan, St Clair RM, Vilinsky I, Deitcher DL (2004) Morphology and molecular organization of the adult neuromuscular junction of Drosophila. J Comp Neurol 468:596–613CrossRefPubMedGoogle Scholar
  61. Pielage J, Cheng L, Fetter RD et al. (2008) A presynaptic giant ankyrin stabilizes the NMJ through regulation of presynaptic microtubules and transsynaptic cell adhesion. Neuron 58:195–209CrossRefPubMedGoogle Scholar
  62. Pielage J, Fetter RD and Davis GW (2005) Presynaptic spectrin is essential for synapse stabilization. Curr Biol 15:918–928CrossRefPubMedGoogle Scholar
  63. Prokop A, Martin-Bermudo MD, Bate M et al. (1998) Absence of PS integrins or laminin A affects extracellular adhesion, but not intracellular assembly, of hemiadherens and neuromuscular junctions in Drosophila embryos. Dev Biol 196:58–76CrossRefPubMedGoogle Scholar
  64. Raghavan S and White RA (1997) Connectin mediates adhesion in Drosophila. Neuron 18:873–880CrossRefPubMedGoogle Scholar
  65. Ritzenthaler S and Chiba A (2003) Myopodia (postsynaptic filopodia) participate in synaptic target recognition. J Neurobiol 55:31–40CrossRefPubMedGoogle Scholar
  66. Ritzenthaler S, Suzuki E and Chiba A (2000) Postsynaptic filopodia in muscle cells interact with innervating motoneuron axons. Nat Neurosci 3:1012–1017CrossRefPubMedGoogle Scholar
  67. Rose D and Chiba A (1999) A single growth cone is capable of integrating simultaneously presented and functionally distinct molecular cues during target recognition. J Neurosci 19:4899–4906PubMedGoogle Scholar
  68. Rose D, Zhu X, Kose H et al. (1997) Toll, a muscle cell surface molecule, locally inhibits synaptic initiation of the RP3 motoneuron growth cone in Drosophila. Development 124:1561–1571PubMedGoogle Scholar
  69. Salinas PC and Price SR (2005) Cadherins and catenins in synapse development. Curr Opin Neurobiol 15:73–80CrossRefPubMedGoogle Scholar
  70. Sanchez-Soriano N and Prokop A (2005) The influence of pioneer neurons on a growing motor nerve in Drosophila requires the neural cell adhesion molecule homolog FasciclinII. J Neurosci 25:78–87CrossRefPubMedGoogle Scholar
  71. Schmid A, Chiba A and Doe CQ (1999) Clonal analysis of Drosophila embryonic neuroblasts: neural cell types, axon projections and muscle targets. Development 126:4653–4689PubMedGoogle Scholar
  72. Schmucker D, Clemens JC, Shu H et al. (2000) Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101:671–684CrossRefPubMedGoogle Scholar
  73. Schuster CM, Davis GW, Fetter RD et al. (1996a) Genetic dissection of structural and functional components of synaptic plasticity. I. Fasciclin II controls synaptic stabilization and growth. Neuron 17:641–654CrossRefPubMedGoogle Scholar
  74. Schuster CM, Davis GW, Fetter RD et al. (1996b) Genetic dissection of structural and functional components of synaptic plasticity. II. Fasciclin II controls presynaptic structural plasticity. Neuron 17:655–667CrossRefPubMedGoogle Scholar
  75. Shishido E, Takeichi M and Nose A (1998) Drosophila synapse formation: regulation by transmembrane protein with Leu-rich repeats, CAPRICIOUS. Science 280:2118–2121CrossRefPubMedGoogle Scholar
  76. Siegler MVS and Jia XX (1999) Engrailed negatively regulates the expression of cell adhesion molecules connectin and neuroglian in embryonic Drosophila nervous system. Neuron 22:265–276CrossRefPubMedGoogle Scholar
  77. Suzuki E, Rose D and Chiba A (2000) The ultrastructural interactions of identified pre- and postsynaptic cells during synaptic target recognition in Drosophila embryos. J Neurobiol 42:448–459CrossRefPubMedGoogle Scholar
  78. Suzuki SC and Takeichi M (2008) Cadherins in neuronal morphogenesis and function. Dev Growth Differ 50 Suppl 1:S119–130Google Scholar
  79. Taniguchi H, Shishido E, Takeichi M et al. (2000) Functional dissection of drosophila capricious: its novel roles in neuronal pathfinding and selective synapse formation. J Neurobiol 42:104–116CrossRefPubMedGoogle Scholar
  80. Thomas U, Ebitsch S, Gorczyca M et al. (2000) Synaptic targeting and localization of discs-large is a stepwise process controlled by different domains of the protein. Curr Biol 10:1108–1117CrossRefPubMedGoogle Scholar
  81. Thomas U, Kim E, Kuhlendahl S et al. (1997) Synaptic clustering of the cell adhesion molecule fasciclin II by discs-large and its role in the regulation of presynaptic structure. Neuron 19:787–799CrossRefPubMedGoogle Scholar
  82. Uhm CS, Neuhuber B, Lowe B et al. (2001) Synapse-forming axons and recombinant agrin induce microprocess formation on myotubes. J Neurosci 21:9678–9689PubMedGoogle Scholar
  83. van Vactor DV, Sink H, Fambrough D et al. (1993) Genes that control neuromuscular specificity in Drosophila. Cell 73:1137–1153CrossRefPubMedGoogle Scholar
  84. Volk T, Fessler LI and Fessler JH (1990) A role for integrin in the formation of sarcomeric cytoarchitecture. Cell 63:525–536CrossRefPubMedGoogle Scholar
  85. Winberg ML, Noordermeer JN, Tamagnone L et al. (1998) Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell 95:903–916CrossRefPubMedGoogle Scholar
  86. Woods DF, Hough C, Peel D et al. (1996) Dlg protein is required for junction structure, cell polarity, and proliferation control in Drosophila epithelia. J Cell Biol 134:1469–1482CrossRefPubMedGoogle Scholar
  87. Wright TR (1960) The phenogenetics of the embryonic mutant, lethal myospheroid, in Drosophila melanogaster. J Exp Zool 143:77–99CrossRefPubMedGoogle Scholar
  88. Yonekura S, Ting C-Y, Neves G et al. (2006) The variable transmembrane domain of Drosophila N-cadherin regulates adhesive activity. Mol Cell Biol 26:6598–6608CrossRefPubMedGoogle Scholar
  89. Yu HH, Huang AS and Kolodkin AL (2000) Semaphorin-1a acts in concert with the cell adhesion molecules fasciclin II and connectin to regulate axon fasciculation in Drosophila. Genetics 156:723–731PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of BiologyUniversity of Puerto RicoMayagüez

Personalised recommendations