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Wnts and TGFβ in synaptogenesis: old friends signalling at new places

Key Points

  • The development and functioning of synaptic junctions requires positional information, which coordinates the correct placement of pre- and postsynaptic elements. This review focuses on new evidence that molecules such as Wnt and transforming growth factor β (TGFβ), which provide positional information during morphogenesis, also promote the differentiation of synapses.

  • At the vertebrate neuromuscular junction (NMJ), the heparan sulphate proteoglycan Agrin is thought to provide an early signal to lay down the postsynaptic machinery. However, its function in central synapses has remained unclear, and additional factors seem to be required for the formation of glutamatergic, cholinergic and GABA (γ-aminobutyric acid) synapses.

  • During early embryonic development, several secreted proteins and their receptors provide positional information that determines the polarity of body structures. For example, a Drosophila Wnt protein, Wingless (Wg), defines anterior-posterior polarity within a body segment.

  • Recent studies in the mammalian nervous system have shown that Wnt proteins might work as signalling factors that induce presynaptic differentiation in the central nervous system. In the developing cerebellum, multi-synaptic glomerular rosettes are formed as mossy fibres establish synaptic connections with granule cell neurons, and Wnt7a seems to act as a retrograde signal that promotes the maturation of the presynaptic cell.

  • In Drosophila, Wg is secreted by synaptic terminals, and it seems to act as an anterograde signal for synapse formation. It signals the differentiation of both pre- and postsynaptic surfaces.

  • Recent studies also indicate that the TGFβ signal transduction pathway forms part of a feedback mechanism during synapse formation at the Drosophila NMJ. Evidence for an involvement of TGFβ family members in synapse development and plasticity has also been provided by studies of the marine mollusc Aplysia.

  • The mechanisms by which Wnt and TGFβ control the transmission of messages across the synapse are not yet fully understood, but they could function by altering the number or localization of receptors, or by regulating receptor-ligand complex turnover. These emerging roles for Wnt and TGFβ will usher in a new level of investigation into the molecular mechanisms of synaptic plasticity.

Abstract

The formation of mature synaptic connections involves the targeted transport and aggregation of synaptic vesicles, the gathering of presynaptic release sites and the clustering of postsynaptic neurotransmitter receptors and ion channels. Positional cues are required to orient the cytoskeleton in the direction of neuronal outgrowth, and also to direct the juxtaposition of synaptic protein complexes at the pre- and postsynaptic membranes. Both anterograde and retrograde factors are thought to contribute positional information during synaptic differentiation, and recent studies in vertebrates and invertebrates have begun to uncover a new role in this process for proteins that are essential for pattern formation in the early embryo.

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Figure 1: The Wnt and TGFβ signalling pathways.
Figure 2: Wingless signalling is essential for the proper formation of pre- and postsynaptic specializations at the fly neuromuscular junction.
Figure 3: Events during new synapse formation at the Drosophila neuromuscular junction, and the role of Wnt and TGFβ pathway in these processes.

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References

  1. Poo, M. M. Neurotrophins as synaptic modulators. Nature Rev. Neurosci. 2, 24–32 (2001).

    Article  CAS  Google Scholar 

  2. Petersen, S. A., Fetter, R. D., Noordermeer, J. N., Goodman, C. S. & DiAntonio, A. Genetic analysis of glutamate receptors in Drosophila reveals a retrograde signal regulating presynaptic transmitter release. Neuron 19, 1237–1248 (1997). An important early account of the involvement of postsynaptic neurotransmitter receptors in retrograde signalling at Drosophila synapses. This article established that presynaptic transmitter release could be affected by regulating the size of postsynaptic responses.

    Article  CAS  Google Scholar 

  3. Davis, G. W. & Goodman, C. S. Synapse-specific control of synaptic efficacy at the terminals of a single neuron. Nature 392, 82–86 (1998).

    Article  CAS  Google Scholar 

  4. Paradis, S., Sweeney, S. T. & Davis, G. W. Homeostatic control of presynaptic release is triggered by postsynaptic membrane depolarization. Neuron 30, 737–749 (2001).

    Article  CAS  Google Scholar 

  5. Tao, H. W. & Poo, M. Retrograde signaling at central synapses. Proc. Natl Acad. Sci. USA 98, 11009–11015 (2001).

    Article  CAS  Google Scholar 

  6. Sanes, J. R. & Lichtman, J. W. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nature Rev. Neurosci. 2, 791–805. (2001). An excellent review on the initial signals involved in the reorganization of the postsynaptic apparatus at vertebrate cholinergic synapses.

    Article  CAS  Google Scholar 

  7. Gautam, M. et al. Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell 85, 525–535 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Pun, S. et al. An intrinsic distinction in neuromuscular junction assembly and maintenance in different skeletal muscles. Neuron 34, 357–370 (2002).

    Article  CAS  Google Scholar 

  11. Smith, M. A. & Hilgenberg, L. G. Agrin in the CNS: a protein in search of a function? Neuroreport 13, 1485–1495 (2002).

    Article  CAS  Google Scholar 

  12. Serpinskaya, A. S., Feng, G., Sanes, J. R. & Craig, A. M. Synapse formation by hippocampal neurons from agrin-deficient mice. Dev. Biol. 205, 65–78 (1999).

    Article  CAS  Google Scholar 

  13. Li, Z., Hilgenberg, L. G., O'Dowd, D. K. & Smith, M. A. Formation of functional synaptic connections between cultured cortical neurons from agrin-deficient mice. J. Neurobiol. 39, 547–557 (1999).

    Article  CAS  Google Scholar 

  14. Ferreira, A. Abnormal synapse formation in agrin-depleted hippocampal neurons. J. Cell Sci. 112, 4729–4738 (1999).

    CAS  Google Scholar 

  15. Bose, C. M. et al. Agrin controls synaptic differentiation in hippocampal neurons. J. Neurosci. 20, 9086–9095 (2000).

    Article  CAS  Google Scholar 

  16. Gingras, J., Rassadi, S., Cooper, E. & Ferns, M. Agrin plays an organizing role in the formation of sympathetic synapses. J. Cell Biol. 158, 1109–1118 (2002).

    Article  CAS  Google Scholar 

  17. Dalva, M. B. et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945–956 (2000).

    Article  CAS  Google Scholar 

  18. Hall, A. C., Lucas, F. R. & Salinas, P. C. Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell 100, 525–535 (2000). This is the first demonstration that a Wnt family member can act as a retrograde synaptogenic signal at mammalian central synapses.

    Article  CAS  Google Scholar 

  19. Krylova, O. et al. WNT-3, expressed by motoneurons, regulates terminal arborization of neurotrophin-3-responsive spinal sensory neurons. Neuron 35, 1043–1056 (2002). This study demonstrates for the first time that different Wnt family members exhibit tissue specificity in the mammalian central nervous system. Wnt3, but not Wnt7 or other Wnts, was shown to serve as a retrograde signal during formation of specific sensory-motor neuron connections in the mouse spinal cord.

    Article  CAS  Google Scholar 

  20. Packard, M. et al. The Drosophila Wnt, wingless, provides an essential signal for pre- and postsynaptic differentiation. Cell 111, 319–330 (2002). Using the glutamatergic Drosophila NMJ system, this study provides important in vivo evidence for the involvement of Wnt signalling in an anterograde manner during synapse formation and differentiation.

    Article  CAS  Google Scholar 

  21. Marques, G. et al. The Drosophila BMP type II receptor wishful thinking regulates neuromuscular synapse morphology and function. Neuron 33, 529–543 (2002). This study identifies Wit as a BMP type II receptor, and suggests a role for Wit in Drosophila NMJ assembly and function. The authors also report convincing evidence that Wit is required presynaptically, implying that its ligand is probably secreted by the postsynaptic muscle surface.

    Article  CAS  Google Scholar 

  22. Aberle, H. et al. wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila. Neuron 33, 545–558. (2002). This study identifies wit as a gene that positively regulates synaptic growth. The study provides crucial genetic evidence for the involvement of TGFβ signalling at this glutamatergic synapse.

    Article  CAS  Google Scholar 

  23. Sweeney, S. T. & Davis, G. W. Unrestricted synaptic growth in spinster — a late endosomal protein implicated in TGF-β-mediated synaptic growth regulation. Neuron 36, 403–416 (2002).

    Article  CAS  Google Scholar 

  24. Dubois, L., Lecourtois, M., Alexandre, C., Hirst, E. & Vincent, J. P. Regulated endocytic routing modulates wingless signaling in Drosophila embryos. Cell 105, 613–624 (2001).

    Article  CAS  Google Scholar 

  25. Pfeiffer, S., Alexandre, C., Calleja, M. & Vincent, J. P. The progeny of wingless-expressing cells deliver the signal at a distance in Drosophila embryos. Curr. Biol. 10, 321–324 (2000).

    Article  CAS  Google Scholar 

  26. Pfeiffer, S., Ricardo, S., Manneville, J. B., Alexandre, C. & Vincent, J. P. Producing cells retain and recycle Wingless in Drosophila embryos. Curr. Biol. 12, 957–962 (2002).

    Article  CAS  Google Scholar 

  27. Moline, M. M., Southern, C. & Bejsovec, A. Directionality of wingless protein transport influences epidermal patterning in the Drosophila embryo. Development 126, 4375–4384 (1999). This study demonstrates the importance of endocytosis in regulating a normal distribution of Wg across embryonic epithelia. The authors achieved this by generating a transgene that expressed a dominant negative form of the Drosophila dynamin shibire.

    CAS  Google Scholar 

  28. Dierick, H. & Bejsovec, A. Cellular mechanisms of wingless/Wnt signal transduction. Curr. Top. Dev. Biol. 43, 153–190 (1999).

    Article  CAS  Google Scholar 

  29. Lawrence, P. A. Wingless signalling: more about the Wingless morphogen. Curr. Biol. 11, R638–639 (2001).

    Article  CAS  Google Scholar 

  30. Cadigan, K. M., Fish, M. P., Rulifson, E. J. & Nusse, R. Wingless repression of Drosophila frizzled 2 expression shapes the Wingless morphogen gradient in the wing. Cell 93, 767–777 (1998).

    Article  CAS  Google Scholar 

  31. Day, S. J. & Lawrence, P. A. Measuring dimensions: the regulation of size and shape. Development 127, 2977–2987 (2001).

    Google Scholar 

  32. Massague, J. How cells read TGF-β signals. Nature Rev. Mol. Cell Biol. 1, 169–178 (2000).

    Article  CAS  Google Scholar 

  33. Wodarz, A. & Nusse, R. Mechanisms of Wnt signaling in development. Annu. Rev. Cell Dev. Biol. 14, 59–88 (1998).

    Article  CAS  Google Scholar 

  34. Theisen, H., Haerry, T. E., O'Connor, M. B. & Marsh, J. L. Developmental territories created by mutual antagonism between Wingless and Decapentaplegic. Development 122, 3939–3948 (1996).

    CAS  Google Scholar 

  35. Nusse, R. & Varmus, H. E. Wnt genes. Cell 69, 1073–1087 (1992).

    Article  CAS  Google Scholar 

  36. Katoh, M. WNT3-WNT14B and WNT3A-WNT14 gene clusters (Review). Int. J. Mol. Med. 9, 579–584 (2002).

    CAS  Google Scholar 

  37. Liu, T. et al. G protein signaling from activated rat frizzled-1 to the β-catenin-Lef-Tcf pathway. Science 292, 1718–1722 (2001).

    Article  CAS  Google Scholar 

  38. Wehrli, M. et al. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407, 527–530 (2000).

    Article  CAS  Google Scholar 

  39. Tamai, K. et al. LDL-receptor-related proteins in Wnt signal transduction. Nature 407, 530–535 (2000).

    Article  CAS  Google Scholar 

  40. Aberle, H., Bauer, A., Stappert, J., Kispert, A. & Kemler, R. β-Catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 16, 3797–3804 (1997).

    Article  CAS  Google Scholar 

  41. Orford, K., Crockett, C., Jensen, J. P., Weissman, A. M. & Byers, S. W. Serine phosphorylation-regulated ubiquitination and degradation of β-catenin. J. Biol. Chem. 272, 24735–24738 (1997).

    Article  CAS  Google Scholar 

  42. Kitagawa, M. et al. An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of β-catenin. EMBO J. 18, 2401–2410 (1999).

    Article  CAS  Google Scholar 

  43. Sun, T. Q. et al. PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling. Nature Cell Biol. 3, 628–636 (2001).

    Article  CAS  Google Scholar 

  44. Chan, S. K. & Struhl, G. Evidence that Armadillo transduces Wingless by mediating nuclear export or cytosolic activation of Pangolin. Cell 111, 265–280 (2002).

    Article  CAS  Google Scholar 

  45. Nathke, I. S., Adams, C. L., Polakis, P., Sellin, J. H. & Nelson, W. J. The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. J. Cell Biol. 134, 165–179 (1996).

    Article  CAS  Google Scholar 

  46. Zumbrunn, J., Kinoshita, K., Hyman, A. A. & Nathke, I. S. Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 β phosphorylation. Curr. Biol. 11, 44–49 (2001).

    Article  CAS  Google Scholar 

  47. 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  Google Scholar 

  48. Conacci-Sorrell, M. E. et al. Nr-CAM is a target gene of the β-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis. Genes Dev. 16, 2058–2072 (2002).

    Article  CAS  Google Scholar 

  49. Massague, J. TGF-β signal transduction. Annu. Rev. Biochem. 67, 753–791 (1998).

    Article  CAS  Google Scholar 

  50. Raftery, L. A., Twombly, V., Wharton, K. & Gelbart, W. M. Genetic screens to identify elements of the decapentaplegic signaling pathway in Drosophila. Genetics 139, 241–254 (1995).

    CAS  Google Scholar 

  51. Savage, C. et al. Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor β pathway components. Proc. Natl Acad. Sci. USA 93, 790–794 (1996).

    Article  CAS  Google Scholar 

  52. Newfeld, S. J., Wisotzkey, R. G. & Kumar, S. Molecular evolution of a developmental pathway: phylogenetic analyses of transforming growth factor-β family ligands, receptors and Smad signal transducers. Genetics 152, 783–795 (1999).

    CAS  Google Scholar 

  53. Lorentzon, M., Hoffer, B., Ebendal, T., Olson, L. & Tomac, A. Habrec1, a novel serine/threonine kinase TGF-β type I-like receptor, has a specific cellular expression suggesting function in the developing organism and adult brain. Exp. Neurol. 142, 351–360 (1996).

    Article  CAS  Google Scholar 

  54. Mehler, M. F., Mabie, P. C., Zhang, D. & Kessler, J. A. Bone morphogenetic proteins in the nervous system. Trends Neurosci. 20, 309–317 (1997).

    Article  CAS  Google Scholar 

  55. Withers, G. S., Higgins, D., Charette, M. & Banker, G. Bone morphogenetic protein-7 enhances dendritic growth and receptivity to innervation in cultured hippocampal neurons. Eur. J. Neurosci. 12, 106–116 (2000).

    Article  CAS  Google Scholar 

  56. Koh, Y. H., Gramates, L. S. & Budnik, V. Drosophila larval neuromuscular junction: molecular components and mechanisms underlying synaptic plasticity. Microsc. Res. Tech. 49, 14–25 (2000).

    Article  CAS  Google Scholar 

  57. Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993).

    CAS  Google Scholar 

  58. Tejedor, F. J. et al. Essential role for dlg in synaptic clustering of Shaker K+ channels in vivo. J. Neurosci. 17, 152–159 (1997).

    Article  CAS  Google Scholar 

  59. Thomas, U. et al. Synaptic clustering of the cell adhesion molecule Fasciclin II by Discs-Large and its role in the regulation of presynaptic structure. Neuron 19, 787–799 (1997).

    Article  CAS  Google Scholar 

  60. Roos, J., Hummel, T., Ng, N., Klambt, C. & Davis, G. W. Drosophila Futsch regulates synaptic microtubule organization and is necessary for synaptic growth. Neuron 26, 371–382 (2000).

    Article  CAS  Google Scholar 

  61. Tsuneizumi, K. et al. Daughters against dpp modulates dpp organizing activity in Drosophila wing development. Nature 389, 627–631. (1997).

    Article  CAS  Google Scholar 

  62. Inoue, H. et al. Interplay of signal mediators of Decapentaplegic (Dpp): molecular characterization of Mothers against dpp, Medea, and Daughters against dpp. Mol. Biol. Cell 9, 2145–2156 (1998).

    Article  CAS  Google Scholar 

  63. Schuman, E. M. Synapse specificity and long-term information storage. Neuron 18, 339–342 (1997).

    Article  CAS  Google Scholar 

  64. Zhang, F., Endo, S., Cleary, L. J., Eskin, A. & Byrne, J. H. Role of transforming growth factor-β in long-term synaptic facilitation in Aplysia. Science 275, 1318–1320 (1997).

    Article  CAS  Google Scholar 

  65. Mayford, M. & Kandel, E. R. Genetic approaches to memory storage. Trends Genet. 15, 463–470 (1999).

    Article  CAS  Google Scholar 

  66. Bailey, C. H. & Kandel, E. R. Structural changes accompanying memory storage. Annu. Rev. Physiol. 55, 397–426 (1993).

    Article  CAS  Google Scholar 

  67. Wainwright, M. L., Zhang, H., Byrne, J. H. & Cleary, L. J. Localized neuronal outgrowth induced by long-term sensitization training in aplysia. J. Neurosci. 22, 4132–4141 (2002).

    Article  CAS  Google Scholar 

  68. Liu, Q. R. et al. A developmental gene (Tolloid/BMP-1) is regulated in Aplysia neurons by treatments that induce long-term sensitization. J. Neurosci. 17, 755–764 (1997).

    Article  CAS  Google Scholar 

  69. Chin, J., Angers, A., Cleary, L. J., Eskin, A. & Byrne, J. H. Transforming growth factor β1 alters synapsin distribution and modulates synaptic depression in Aplysia. J. Neurosci. 22, RC220 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank M. Gorczyca and C. Ruiz-Canada, and to D. Gorczyca for careful reading of the manuscript and helpful discussions.

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Correspondence to Vivian Budnik.

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DATABASES

Entrez

Tbl1

FlyBase

Arm

Arr

Babo

Dad

DFz2

Dlg

Dpp

Dsh

Fas2

mad

Med

Put

Sax

Shaggy

shi

Spin

Tkv

Wg

Wit

LocusLink

Agrin

β-catenin

γ-catenin

Fz1

Fz2

Go

Gq

Gsk3β

Lef

LRP

Map1b

NrCAM

sFrp1

sma

Smad4

synapsin I

Tcf

TGFβ

Wnt

Swiss-Prot

Apc

Axin

Fz

FURTHER INFORMATION

Encyclopedia of Life Sciences

bone morphogenetic proteins and their receptors

developmental biology and synapse formation

G protein-coupled receptors

G proteins

serotonin

transforming growth factor β

Glossary

ACTIVE ZONE

A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It constitutes the site of synaptic vesicle clustering, docking and transmitter release.

HEPARAN SULPHATE

A glycosaminoglycan that consists of repeated units of hexuronic acid and glucosamine residues. It usually attaches to proteins through a xylose residue to form proteoglycans.

ANTISENSE

A single-stranded RNA molecule whose sequence is complementary to that of the mRNA for a given gene. It can bind to the mRNA, thereby preventing it from being translated.

EPHRINS

A families of molecules that, by interacting with their Eph receptors, mediate cell-contact-dependent signalling, and are primarily involved in the generation and maintenance of patterns of cellular organization. They accomplish this goal by the control of repulsion at a boundary or gradient, or by upregulating cell adhesion.

TRANSCYTOSIS

Transport of macromolecules across a cell, consisting of endocytosis of a macromolecule at one side of a monolayer and exocytosis at the other side.

IMAGINAL DISC

Single-cell layer epithelial structures of the Drosophila larva that give rise to wings, legs and other appendages.

DYNAMIN

A GTPase that takes part in endocytosis. It seems to be involved in severing the connection between the nascent vesicle and the donor membrane.

GAL4/UAS SYSTEM

A genetic system for controlling the induction of gene expression. An activator line that expresses the yeast transcriptional activator GAL4 gene under the control of the heat-shock 70 promoter (hsp70) or a tissue-specific promoter is crossed to an effector line that carries the DNA-binding motif of Gal4 (UAS) fused to the gene of interest. As a result, the progeny of this cross expresses the gene of interest in an activator-specific manner.

SHAKER K+ CHANNEL

A voltage-gated channel, the activation of which leads to the appearance of a transient K+ current. It takes its name from Drosophila with mutations in the gene that encodes this protein. These flies display a violent shaking phenotype when under anaesthesia.

REVERSE GENETICS

Genetic analysis that proceeds from genotype to phenotype through gene-manipulation techniques.

FORWARD GENETICS

A genetic analysis that proceeds from phenotype to genotype by positional cloning or candidate-gene analysis.

LONG-TERM FACILITATION

(LTF). A lasting increase in the strength of synapses between sensory and motor neurons in Aplysia. LTF is the cellular mechanism that underlies non-associative learning and memory. LTF results largely from presynaptic changes. It is similar to the LTP of the hippocampal mossy fibre pathway, but differs from LTP in other regions of the hippocampus, which are associative.

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Packard, M., Mathew, D. & Budnik, V. Wnts and TGFβ in synaptogenesis: old friends signalling at new places. Nat Rev Neurosci 4, 113–120 (2003). https://doi.org/10.1038/nrn1036

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