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WIREs Dev Biol
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Advances in synapse formation: forging connections in the worm

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Abstract Synapse formation is the quintessential process by which neurons form specific connections with their targets to enable the development of functional circuits. Over the past few decades, intense research efforts have identified thousands of proteins that localize to the pre‐ and postsynaptic compartments. Genetic dissection has provided important insights into the nexus of the molecular and cellular network, and has greatly advanced our knowledge about how synapses form and function physiologically. Moreover, recent studies have highlighted the complex regulation of synapse formation with the identification of novel mechanisms involving cell interactions from non‐neuronal sources. In this review, we cover the conserved pathways required for synaptogenesis and place specific focus on new themes of synapse modulation arising from studies in Caenorhabditis elegans. WIREs Dev Biol 2015, 4:85–97. doi: 10.1002/wdev.165 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Signaling Pathways > Cell Fate Signaling Nervous System Development > Worms
Epidermal regulation of synapse formation. (a) Illustration of AIY synapses in the head (brown). AIY and RIA reside in the nerve ring anterior to the posterior bulb of the pharynx (gray outline). AIY makes synapses (red) onto RIA at reliable, discrete locations. A zoomed‐in view is illustrated in (b) and (c). (b) Synapses from AIY onto RIA are modulated by adjacent glial cells, which limit the placement of presynaptic terminals. The epidermis, which is in close proximity to the glial cells, regulates their morphology through EGL‐15. Through the interaction of EGL‐15 on the epidermis and a yet to be identified binding partner in glial cells, the epidermis is able to restrict the morphology into a discrete region adjacent to AIY presynaptic terminals. In wild type animals, EGL‐15 expression is mediated by CIMA‐1, most likely through lysosomal degradation. (c) In cima‐1(lf) mutants, EGL‐15 is more highly expressed compared to wild type, possibly leading to an elongated region of interaction. In turn, the contact between AIY and the glial cells is also expanded, leading to an increase in presynaptic terminals from AIY onto RIA. One potential explanation for this alteration of presynaptic terminals could be through an increased signaling of UNC‐6.
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Non‐neuronal cells modulate synaptogenesis through secreted and cell‐adhesion molecules. Upon binding to epithelial SYG‐2, SYG‐1 localized in the HSN signals through WVE‐1 to increase actin polymerization. In an analogous pathway, in the nerve ring, secreted UNC‐6 from glial cells stimulates UNC‐40 expressed in AIY, which then actives a cascade of CED‐5, CED‐10, and MIG‐10. MIG‐10 interacts with ABI‐1, a member of the WAVE complex that directs cytoskeletal remodeling. In the case of the HSN pathway (blue proteins), actin polymerization facilitates the recruitment of SYD‐1, SYD‐2, and downstream active zone proteins to the dense projection (red) through the actin‐binding protein, NAB‐1. The glial/nerve ring pathway (green proteins) induces actin polymerization, which is required for synaptic vesicle localization; however, actin polymerization appears to be dispensable for the recruitment of SYD‐1 and SYD‐2 to the active zone in this case, suggesting an alternative mechanism. Black arrows represent signaling events; white arrows represent protein complex recruitment.
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Synapse specification at the neuromuscular junction. Acetylcholine receptors are clustered at the neuromuscular junction through at least two different pathways. First, the muscles can cell‐autonomously enhance acetylcholine receptor clustering through the expression of LEV‐10 and its secreted binding protein LEV‐9. This complex is also aided by OIG‐4, secreted by muscle. A second pathway requires the cholinergic terminals and MADD‐4 to enforce acetylcholine receptor clustering. Cholinergic neurons secrete the MADD‐4 long isoform (MADD‐4 L), which through an unknown mechanism causes acetylcholine receptor clustering at the neuromuscular junction. Cholinergic neurons also assist with the clustering of GABA receptors. Through the secretion of MADD‐4B short isoform, both GABAergic neurons and cholinergic neurons increase GABA receptor clustering. It is thought that the proper postsynaptic clustering of receptors adjacent to their respective presynaptic terminals is mediated through some heterophilic interaction between MADD‐4 isoforms. Since GABA receptors cluster in the absence of MADD‐4B, albeit adjacent to cholinergic terminals, this suggests that other molecules are required for the clustering of GABA receptors.
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Regulation of synapse formation by the RPM‐1 signaling network. RPM‐1 ensures proper synapse formation by signaling through multiple binding partners through its RCC1 (yellow), PHR (red), B‐Box (blue), and RING (orange) domains. RPM‐1 E3 ligase activity, via binding to FSN‐1, inhibits the DLK‐1 MAPK cascade, which in the absence of RPM‐1 disrupts proper synapse formation. PPM‐1 may prevent aberrant synapse formation through the dephosphorylation of PMK‐3 substrates, such as CEBP‐1. ANC‐1 binds to RPM‐1 and functions downstream through WNT signaling and BAR‐1 (β‐catenin) to maintain proper synapse morphology. Through GLO‐4 binding, RPM‐1 may activate GLO‐1 and APM‐3, directly or indirectly, to regulate synaptic endosomes. RPM‐1 binding to RAE‐1 may regulate synapse formation by stabilizing microtubules. Solid arrows and lines represent activating or inhibiting signaling events, respectively. Dashed line represents unknown signaling events that regulate synaptic morphology.
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The active zone and core components of presynaptic terminals. (a) 3D electron tomography reconstructions of a presynaptic bouton at the neuromuscular junction in wild type and syd‐2(lf) backgrounds. Synaptic vesicles (blue) are docked at the membrane adjacent to the dense projection (red). Dense core vesicles (black) are mixed among the reserve pool of synaptic vesicles. (Reprinted with permission from Ref . Copyright 2013 The Rockefeller University Press) (b) Electron tomography and schematic rendering of bays formed by the presynaptic density and associated synaptic vesicles. The view of bays is shown as parallel to the plasma membrane. (Reprinted with permission from Ref . Copyright 2013 yyy) (c) Schematics of active zone assembly: SYD‐1 and SYD‐2 are recruited to the active zone. SYD‐2 binding to ELKS‐1 directs UNC‐10 and UNC‐13 to the active zone. RSY‐1 exerts a negative role on SYD‐2 and ELKS‐1 interaction. Through UNC‐10 and UNC‐13, synaptic vesicles are then docked at the active zone. SAD‐1 and PAR‐4 enhance proper synaptic organization likely by regulating vesicle localization. Orange proteins are core components, green proteins are positive regulators of synapse formation, and the blue protein is a negative regulator of synapse formation. Black arrows and lines represent signaling; white arrows represent protein complex recruitment.
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Nervous System Development > Worms
Signaling Pathways > Cell Fate Signaling
Gene Expression and Transcriptional Hierarchies > Cellular Differentiation