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WNTs tune up the neuromuscular junction

Nature Reviews Neuroscience volume 10, pages 627–634 (2009)Cite this article

Abstract

Although WNTs have been long thought of as regulators of cell fate, recent studies highlight their involvement in crucial aspects of synaptic development in the nervous system. Particularly compelling are recent studies of the neuromuscular junction in nematodes, insects, fish and mammals. These studies place WNTs as major determinants of synapse differentiation and neurotransmitter receptor clustering.

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Figure 1: Role of WNTs in AChR clustering at the vertebrate neuromuscular junction.
Figure 2: Role of WNTs during Drosophila melanogaster larval neuromuscular junction development.
Figure 3: Inhibitory role of WNT signalling at the neuromuscular junction of Caenorhabditis elegans.

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References

  1. Siegfried, E. & Perrimon, N. Drosophila wingless: a paradigm for the function and mechanism of Wnt signaling. Bioessays 16, 395–404 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Gould, T. D. & Manji, H. K. The Wnt signaling pathway in bipolar disorder. Neuroscientist 8, 497–511 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. De Ferrari, G. V. & Inestrosa, N. C. Wnt signaling function in Alzheimer's disease. Brain Res. Brain Res. Rev. 33, 1–12 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Caricasole, A. et al. Two sides of the same coin: Wnt signaling in neurodegeneration and neuro-oncology. Biosci. Rep. 25, 309–327 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Inestrosa, N. et al. Wnt signaling involvement in β-amyloid-dependent neurodegeneration. Neurochem. Int. 41, 341–344 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Johnson, M. L. & Rajamannan, N. Diseases of Wnt signaling. Rev. Endocr. Metab. Disord. 7, 41–49 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Speese, S. D. & Budnik, V. Wnts: up-and-coming at the synapse. Trends Neurosci. 30, 268–275 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Salinas, P. C. & Zou, Y. Wnt signaling in neural circuit assembly. Annu. Rev. Neurosci. 31, 339–358 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Song, Y. & Balice-Gordon, R. New dogs in the dogma: Lrp4 and Tid1 in neuromuscular synapse formation. Neuron 60, 526–528 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Widelitz, R. Wnt signaling through canonical and non-canonical pathways: recent progress. Growth Factors 23, 111–116 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Lucas, F. R. & Salinas, P. C. WNT-7a induces axonal remodeling and increases synapsin I levels in cerebellar neurons. Dev. Biol. 192, 31–44 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Krylova, O. et al. WNT-3, expressed by motoneurons, regulates terminal arborization of neurotrophin-3-responsive spinal sensory neurons. Neuron 35, 1043–1056 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Rosso, S. B., Sussman, D., Wynshaw-Boris, A. & Salinas, P. C. Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nature Neurosci. 8, 34–42 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Kummer, T. T., Misgeld, T. & Sanes, J. R. Assembly of the postsynaptic membrane at the neuromuscular junction: paradigm lost. Curr. Opin. Neurobiol. 16, 74–82 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Schaeffer, L., de Kerchove d'Exaerde, A. & Changeux, J. P. Targeting transcription to the neuromuscular synapse. Neuron 31, 15–22 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Sanes, J. R. & Lichtman, J. W. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nature Rev. Neurosci. 2, 791–805 (2001).

    Article  CAS  Google Scholar 

  17. Misgeld, T. et al. Roles of neurotransmitter in synapse formation: development of neuromuscular junctions lacking choline acetyltransferase. Neuron 36, 635–648 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Weston, C. et al. Cooperative regulation by Rac and Rho of agrin-induced acetylcholine receptor clustering in muscle cells. J. Biol. Chem. 278, 6450–6455 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Kim, N. & Burden, S. J. MuSK controls where motor axons grow and form synapses. Nature Neurosci. 11, 19–27 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Lefebvre, J. L., Jing, L., Becaficco, S., Franzini-Armstrong, C. & Granato, M. Differential requirement for MuSK and dystroglycan in generating patterns of neuromuscular innervation. Proc. Natl Acad. Sci. USA 104, 2483–2488 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lin, W. et al. Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 410, 1057–1064 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Bezakova, G., Rabben, I., Sefland, I., Fumagalli, G. & Lomo, T. Neural agrin controls acetylcholine receptor stability in skeletal muscle fibers. Proc. Natl Acad. Sci. USA 98, 9924–9929 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Luo, Z. G. et al. Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1. Neuron 35, 489–505 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Kim, C. H., Xiong, W. C. & Mei, L. Regulation of MuSK expression by a novel signaling pathway. J. Biol. Chem. 278, 38522–38527 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Wang, J. et al. Wnt/β-catenin signaling suppresses Rapsyn expression and inhibits acetylcholine receptor clustering at the neuromuscular junction. J. Biol. Chem. 283, 21668–21675 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Henriquez, J. P. et al. Wnt signaling promotes AChR aggregation at the neuromuscular synapse in collaboration with agrin. Proc. Natl Acad. Sci. USA 105, 18812–18817 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jing, L., Lefebvre, J. L., Gordon, L. R. & Granato, M. Wnt signals organize synaptic prepattern and axon guidance through the zebrafish unplugged/MuSK receptor. Neuron 61, 721–733 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Castelo-Branco, G. et al. Ventral midbrain glia express region-specific transcription factors and regulate dopaminergic neurogenesis through Wnt-5a secretion. Mol. Cell Neurosci. 31, 251–262 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Hooper, J. E. Distinct pathways for autocrine and paracrine Wingless signalling in Drosophila embryos. Nature 372, 461–464 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Li, X. M. et al. Retrograde regulation of motoneuron differentiation by muscle beta-catenin. Nature Neurosci. 11, 262–268 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Wang, J. & LUO, Z.-G. The role of Wnt/ß-catenin signaling in postsynaptic differentiation. Commun. Integr. Biol. 1, 1–3 (2008).

    Article  Google Scholar 

  34. Zhang, B. et al. Beta-catenin regulates acetylcholine receptor clustering in muscle cells through interaction with rapsyn. J. Neurosci. 27, 3968–3973 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ohno, K., Sadeh, M., Blatt, I., Brengman, J. M. & Engel, A. G. E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Hum. Mol. Genet. 12, 739–748 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Deng, J. et al. beta-catenin interacts with and inhibits NF-κB in human colon and breast cancer. Cancer Cell 2, 323–334 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Sanes, J. R. & Lichtman, J. W. Development of the vertebrate neuromuscular junction. Annu. Rev. Neurosci. 22, 389–442 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Svensson, A., Norrby, M., Libelius, R. & Tagerud, S. Secreted frizzled related protein 1 (Sfrp1) and Wnt signaling in innervated and denervated skeletal muscle. J. Mol. Histol 39, 329–337 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Glass, D. J. et al. Agrin acts via a MuSK receptor complex. Cell 85, 513–523 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Weatherbee, S. D., Anderson, K. V. & Niswander, L. A. LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development 133, 4993–5000 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. DeChiara, T. M. et al. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell 85, 501–512 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Kim, N. et al. Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell 135, 334–342 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang, B. et al. LRP4 serves as a coreceptor of agrin. Neuron 60, 285–297 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang, B., Xiong, W. C. & Mei, L. Get ready to Wnt: prepatterning in neuromuscular junction formation. Dev. Cell 16, 325–327 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Wang, J. et al. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. Nature Neurosci. 6, 1017–1018 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Akhmanova, A. & Hoogenraad, C. C. Microtubule plus-end-tracking proteins: mechanisms and functions. Curr. Opin. Cell Biol. 17, 47–54 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Reilein, A. & Nelson, W. J. APC is a component of an organizing template for cortical microtubule networks. Nature Cell Biol. 7, 463–473 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Rosenberg, M. M. et al. Adenomatous polyposis coli plays a key role, in vivo, in coordinating assembly of the neuronal nicotinic postsynaptic complex. Mol. Cell Neurosci. 38, 138–152 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Temburni, M. K., Rosenberg, M. M., Pathak, N., McConnell, R. & Jacob, M. H. Neuronal nicotinic synapse assembly requires the adenomatous polyposis coli tumor suppressor protein. J. Neurosci. 24, 6776–6784 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Broadie, K. & Bate, M. Innervation directs receptor synthesis and localization in Drosophila embryo synaptogenesis. Nature 361, 350–353 (1993).

    Article  CAS  PubMed  Google Scholar 

  51. Featherstone, D. E., Rushton, E. & Broadie, K. Developmental regulation of glutamate receptor field size by nonvesicular glutamate release. Nature Neurosci. 5, 141–146 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Augustin, H., Grosjean, Y., Chen, K., Sheng, Q. & Featherstone, D. E. Nonvesicular release of glutamate by glial xCT transporters suppresses glutamate receptor clustering in vivo. J. Neurosci. 27, 111–123 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Daniels, R. W. et al. A single vesicular glutamate transporter is sufficient to fill a synaptic vesicle. Neuron 49, 11–16 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Liebl, F. L. & Featherstone, D. E. Identification and investigation of Drosophila postsynaptic density homologs. Bioinform Biol. Insights 2, 375–387 (2008).

    Article  CAS  Google Scholar 

  55. Liebl, F. L. & Featherstone, D. E. Genes involved in Drosophila glutamate receptor expression and localization. BMC Neurosci. 6, 44 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Marques, G. & Zhang, B. Retrograde signaling that regulates synaptic development and function at the Drosophila neuromuscular junction. Int. Rev. Neurobiol. 75, 267–285 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Packard, M. et al. The Drosophila wnt, wingless, provides an essential signal for pre- and postsynaptic differentiation. Cell 111, 319–330 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ataman, B. et al. Nuclear trafficking of Drosophila Frizzled-2 during synapse development requires the PDZ protein dGRIP. Proc. Natl Acad. Sci. USA 103, 7841–7846 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gogel, S., Wakefield, S., Tear, G., Klambt, C. & Gordon-Weeks, P. R. The Drosophila microtubule associated protein Futsch is phosphorylated by Shaggy/Zeste-white 3 at an homologous GSK3β phosphorylation site in MAP1B. Mol. Cell Neurosci. 33, 188–199 (2006).

    Article  PubMed  Google Scholar 

  60. Mathew, D. et al. Wingless signaling at synapses is through cleavage and nuclear import of receptor DFrizzled2. Science 310, 1344–1347 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hoogenraad, C. C., Milstein, A. D., Ethell, I. M., Henkemeyer, M. & Sheng, M. GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking. Nature Neurosci. 8, 906–915 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Gomez-Ospina, N., Tsuruta, F., Barreto-Chang, O., Hu, L. & Dolmetsch, R. The C terminus of the L-type voltage-gated calcium channel CaV1.2 encodes a transcription factor. Cell 127, 591–606 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lin, S. Y. et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nature Cell Biol. 3, 802–808 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Baron, M. et al. Multiple levels of Notch signal regulation. Mol. Membr. Biol. 19, 27–38 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Ataman, B. et al. Rapid activity-dependent modifications in synaptic structure and function require bidirectional wnt signaling. Neuron 57, 705–718 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Barco, A., Bailey, C. H. & Kandel, E. R. Common molecular mechanisms in explicit and implicit memory. J. Neurochem. 97, 1520–1533 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Miech, C., Pauer, H. U., He, X. & Schwarz, T. L. Presynaptic local signaling by a canonical wingless pathway regulates development of the Drosophila neuromuscular junction. J. Neurosci. 28, 10875–10884 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Franciscovich, A. L., Mortimer, A. D., Freeman, A. A., Gu, J. & Sanyal, S. Overexpression screen in Drosophila identifies neuronal roles of GSK-3β/shaggy as a regulator of AP-1-dependent developmental plasticity. Genetics 180, 2057–2071 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Liebl, F. L. et al. Derailed regulates development of the Drosophila neuromuscular junction. Dev. Neurobiol. 68, 152–165 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Dixon, S. J. & Roy., P. J. Muscle arm development in Caenorhabditis elegans. Development 132, 3079–3092 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Gally, C., Eimer, S., Richmond, J. E. & Bessereau, J. L. A transmembrane protein required for acetylcholine receptor clustering in Caenorhabditis elegans. Nature 431, 578–582 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Francis, M. M. et al. The Ror receptor tyrosine kinase CAM-1 is required for ACR-16-mediated synaptic transmission at the C. elegans neuromuscular junction. Neuron 46, 581–594 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Ackley, B. D. et al. The basement membrane components nidogen and type XVIII collagen regulate organization of neuromuscular junctions in Caenorhabditis elegans. J. Neurosci. 23, 3577–3587 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Klassen, M. P. & Shen, K. Wnt signaling positions neuromuscular connectivity by inhibiting synapse formation in C. elegans. Cell 130, 704–716 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Ciani, L., Krylova, O., Smalley, M. J., Dale, T. C. & Salinas, P. C. A divergent canonical WNT-signaling pathway regulates microtubule dynamics: dishevelled signals locally to stabilize microtubules. J. Cell Biol. 164, 243–253 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lucas, F. R., Goold, R. G., Gordon-Weeks, P. R. & Salinas, P. C. Inhibition of GSK-3β leading to the loss of phosphorylated MAP-1B is an early event in axonal remodelling induced by WNT-7a or lithium. J. Cell Sci. 111, 1351–1361 (1998).

    CAS  PubMed  Google Scholar 

  77. Zhong, W. Going nuclear is again a winning (Wnt) strategy. Dev. Cell 15, 635–636 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Lyu, J., Yamamoto, V. & Lu, W. Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis. Dev. Cell 15, 773–780 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Drs K. Koles, S. Speese, J. Ashley and P. Ramachandran for comments on the manuscript. V.B. is supported by grant MH70000 from the National Institutes of Health (NIH), USA.

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  1. Ceren Korkut and Vivian Budnik are at The Department of Neurobiology, Aaron Lazare Biomedical Research Building, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA,

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Korkut, C., Budnik, V. WNTs tune up the neuromuscular junction. Nat Rev Neurosci 10, 627–634 (2009). https://doi.org/10.1038/nrn2681

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