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WIREs Dev Biol
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Embryonic and larval neural connectivity: progressive changes in synapse form and function at the neuromuscular junction mediated by cytoskeletal regulation

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Abstract During development, precise formation of millions of synaptic connections is critical for the formation of a functional nervous system. Synaptogenesis is a complex multistep process in which axons follow gradients of secreted and cell surface guidance cues to reach their target area, at which point they must accurately distinguish their specific target. Upon target recognition, the axonal growth cone undergoes rapid growth and morphological changes, ultimately forming a functional synapse that continues to remodel during activity‐dependent plasticity. Significant evidence suggests that the underlying actin and microtubule (MT) cytoskeletons are key effectors throughout synaptogenesis downstream of numerous receptors and signaling pathways. An increasing number of cytoskeletal‐associated proteins have been shown to influence actin and MT stability and dynamics and many of these regulators have been implicated during synaptic morphogenesis using both mammalian and invertebrate model systems. In this review, we present an overview of the role cytoskeletal regulators play during the formation of the Drosophila neuromuscular junction. WIREs Dev Biol 2013, 2:747–765. doi: 10.1002/wdev.114 This article is categorized under: Nervous System Development > Flies

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Anatomy of the Drosophila neuromuscular junction. (a). The Drosophila larval motor system consists of 30 muscle fibers in each abdominal hemisegment that are innervated by 34 motor nerves. (b) During embryonic development, the 34 motor neurons emerge from the central nervous system in two major nerve bundles: the intersegmental nerve (ISN; red, blue, yellow) and segmental nerve (SN; black). From these nerve bundles, secondary branches diverge to innervate specific muscle targets. (c) The ISNb innervates muscles 6 and 7 while SNa innervates muscle 4. Synaptic arbors expand rapidly during larval development by the addition of new synaptic boutons and branches. (d) Bundles of microtubules (MT; blue) run down the length of each synaptic arbor into the terminal bouton, where they can be splayed (in dynamic/growing boutons) or looped (in stable boutons, not shown). Underlying the presynaptic membrane is a branched network of actin filaments (orange), which help localize the components required for neurotransmission (active zones, AZ; yellow). Surrounding the presynaptic terminal is the subsynaptic reticulum (SSR; see inset), an elaborate system of membranous infolding required for proper neurotransmission. (e) Actin (bottom) and MTs (top) are polarized structures, with the addition of G‐actin monomers and tubulin dimers added to the barbed and plus ends, respectively.

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Glutamate receptor localization and clustering at the Drosophila neuromuscular junction (NMJ). The primary neurotransmitter (NT) at the Drosophila NMJ is glutamate. Proper neurotransmission requires glutamate receptors (GluR) clustering in precise apposition to sites of presynaptic vesicle release. Although many of the details through which GluRs localize to and are clustered at the membrane, several components of this process have been identified. Discs‐Large (Dlg), a MAGUK family scaffolding protein, influences the trafficking of GluRIIB but not GluRIIA receptors to the membrane. GluRIIA trafficking is modulated by the 4.1 protein Coracle, which interacts with the spectrin‐actin cytoskeleton. MTs are also thought to play a role in GluR localization, in part through the action of the exocyst protein Sec8. Clustering of GluRs is influenced by aPKC activity. aPKC phosphorylates Bazooka (Baz), which localizes to the membrane and is subsequently dephosphorylated by PTEN. The Baz–PTEN complex formation in turn dephosphorylates several phosphoinositide lipids, which promotes remodeling of the underlying actin network to promote GluR clustering.

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Drosophila LAR (DLAR) signaling at the Drosophila neuromuscular junction (NMJ). The Drosophila receptor protein tyrosine phosphatase DLAR plays a multifaceted role at the NMJ and influence NMJ growth and expansion as well as synaptic activity. DLAR interacts with a variety of signaling partners, including Liprin α, Abl tyrosine kinase, Enabled (Ena), Trio and Rac. DLAR modulates microtubules (MT) dynamics upstream of Trio and the formin Diaphanous (Dia). DLAR also interacts with Abl to regulate both actin and MT dynamics. Abl regulates MT stability via phosphorylation of the MT plus end interacting proteins (MT+TIP) Orbit and influences actin assembly through interactions with Ena, which in turn enhances actin polymerization via profilin. Abl/Ena‐dependent actin assembly is antagonized by the activity of Abi (Abl‐interacting protein). DLAR also interacts with two heparin sulfate proteoglycans, Syndecan (Sdc), and Dallylike (Dlp). Sdc/DLAR interactions promote NMJ growth while Dlp/DLAR interactions function to restrain AZ structure and function. Additionally, the DLAR partner Liprin α influences presynaptic function via Neurabin (NAB‐1). NAB‐1 interacts with both actin and the adhesion protein SYD‐1 to modulate synaptic vesicle (SV) localization at the presynaptic membrane.

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Wnt and bone morphogenic protein (BMP) signaling in Drosophila. (a)Wingless (Wg), the Drosophila Wnt homolog, signals in an anterograde fashion at the neuromuscular junction (NMJ). Released by the neuron, Wg signals via its receptor (DFrizzled2; DFz2) and activates several downstream signaling cascades. In the divergent canonical pathway, DFz2 activates Disheveled (Dvl), which inhibits the GSK3β homolog Shaggy. Shaggy regulates the activity of the microtubules (MT) stabilizing protein Futsch, which in turn modulates MT dynamics to influence NMJ expansion. Alternatively, Wg can signal via the planar cell polarity (PCP) pathway by Dvl‐activation of the small GTPases Rho and Rac, which influences downstream activity of c‐Jun kinase (JNK) to regulate MT stability and transport. (b) In addition to anterograde signaling via Wnt, the retrograde signaling molecule Gbb is released by the postsynaptic muscle to influence presynaptic growth and neurotransmission. Gbb, the Drosophila BMP homolog, signals through a heterotrimeric complex of type I and II BMP receptors (Thick veins, Tkv, and Wishful thinking, Wit). BMP signaling is regulated in part by Spicthyin (Spict), which modulates receptor trafficking to the membrane. Following Gbb binding and receptor complex formation, Tkv phosphorylates and activates Wit, leading to the phosphorylation of the downstream transcription factors Mother Against Decapentaplegic (Mad) and Medea (Med). The Mad/Med complex then translocates to the nucleus along MTs, in part through interactions with the dynactin complex component p150glued. In the nucleus, Mad/Med influences the transcription of target genes, including the RhoGEF Trio, which promotes actin remodeling. BMP signaling also influences actin dynamics through interactions with Nervous Wreck (Nwk), which interacts with Wit in the presynaptic periactive zone to influence NMJ growth and synaptic transmission.

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