Key Points
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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.
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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.
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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.
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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.
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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.
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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.
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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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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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bone morphogenetic proteins and their receptors
Glossary
- ACTIVE ZONE
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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
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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
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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
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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
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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
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Single-cell layer epithelial structures of the Drosophila larva that give rise to wings, legs and other appendages.
- DYNAMIN
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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
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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
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(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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DOI: https://doi.org/10.1038/nrn1036
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