The cell polarity scaffold lethal giant larvae regulates synapse morphology and function

Staples, Jon; Broadie, Kendal

doi:10.1242/jcs.120139

Cited by 10 publications

(13 citation statements)

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“…Null Mgat1 mutants display increased NMJ growth (increased synapse area, branching and bouton number) and function (increased transmission and FM1-43 dye cycling), showing that MGAT1-dependent N-glycosylation plays inhibitory roles in synaptogenesis. Consistent with the hypothesis that a modified synaptomatrix would alter trans-synaptic signaling, WG, GBB and JEB signaling ligands are all disrupted in the absence of Mgat1 function, together with loss in synaptic recruitment of Discs large 1 (DLG1) and Lethal (2) giant larvae [L(2)GL] membrane scaffolds that modulate NMJ synaptogenesis (Humbert et al, 2008;Staples and Broadie, 2013;Wang et al, 2011). Together, these results show requirements for MGAT1-dependent N-glycosylation in transsynaptic signaling and synaptic localization of intracellular scaffolds driving neuromuscular synaptogenesis.…”

Section: Introductionmentioning

confidence: 65%

“…In addition, we have just recently defined Lethal (2) giant larvae [L(2)GL] as another key synaptic scaffold, which presynaptically facilitates the assembly of BRP-containing active zones to regulate SV cycling, and postsynaptically regulates GluR subunit composition (Staples and Broadie, 2013). We hypothesized that, downstream of MGAT1-dependent changes in trans-synaptic signaling, defects in recruiting these synaptic scaffolds could explain changes in pre/postsynaptic molecular composition.…”

Section: Loss Of Key Synaptic Scaffolds Driving Synaptogenesis In Mgamentioning

confidence: 99%

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N-glycosylation requirements in neuromuscular synaptogenesis

et al. 2013

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Neural development requires N-glycosylation regulation of intercellular signaling, but the requirements in synaptogenesis have not been well tested. All complex and hybrid N-glycosylation requires MGAT1 (UDP-GlcNAc:α-3-D-mannoside-β1,2-N-acetylglucosaminyltransferase I) function, and Mgat1 nulls are the most compromised N-glycosylation condition that survive long enough to permit synaptogenesis studies. At the Drosophila neuromuscular junction (NMJ), Mgat1 mutants display selective loss of lectin-defined carbohydrates in the extracellular synaptomatrix, and an accompanying accumulation of the secreted endogenous Mind the gap (MTG) lectin, a key synaptogenesis regulator. Null Mgat1 mutants exhibit strongly overelaborated synaptic structural development, consistent with inhibitory roles for complex/hybrid Nglycans in morphological synaptogenesis, and strengthened functional synapse differentiation, consistent with synaptogenic MTG functions. Synapse molecular composition is surprisingly selectively altered, with decreases in presynaptic active zone Bruchpilot (BRP) and postsynaptic Glutamate receptor subtype B (GLURIIB), but no detectable change in a wide range of other synaptic components. Synaptogenesis is driven by bidirectional trans-synaptic signals that traverse the glycan-rich synaptomatrix, and Mgat1 mutation disrupts both anterograde and retrograde signals, consistent with MTG regulation of trans-synaptic signaling. Downstream of intercellular signaling, pre-and postsynaptic scaffolds are recruited to drive synaptogenesis, and Mgat1 mutants exhibit loss of both classic Discs large 1 (DLG1) and newly defined Lethal (2) giant larvae [L(2)GL] scaffolds. We conclude that MGAT1-dependent N-glycosylation shapes the synaptomatrix carbohydrate environment and endogenous lectin localization within this domain, to modulate retention of trans-synaptic signaling ligands driving synaptic scaffold recruitment during synaptogenesis.

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Section: Introductionmentioning

confidence: 65%

Section: Loss Of Key Synaptic Scaffolds Driving Synaptogenesis In Mgamentioning

confidence: 99%

N-glycosylation requirements in neuromuscular synaptogenesis

et al. 2013

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“…Mutants for dlg specifically lose B-type but not A-type receptors . Another membrane-associated scaffolding protein, Lethal (2) giant larvae (Lgl), has the opposite function, where loss of lgl leads to an increase in B-type, but not A-type receptors (Staples and Broadie 2013). Dlg and Lgl are otherwise known to interact in epithelial cells where they cooperate to specify the basolateral membrane domain (Laprise and Tepass 2011).…”

Section: Ionotropic Glutamate Receptors At the Nmjmentioning

confidence: 99%

Transmission, Development, and Plasticity of Synapses

Harris¹,

2015

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Chemical synapses are sites of contact and information transfer between a neuron and its partner cell. Each synapse is a specialized junction, where the presynaptic cell assembles machinery for the release of neurotransmitter, and the postsynaptic cell assembles components to receive and integrate this signal. Synapses also exhibit plasticity, during which synaptic function and/or structure are modified in response to activity. With a robust panel of genetic, imaging, and electrophysiology approaches, and strong evolutionary conservation of molecular components, Drosophila has emerged as an essential model system for investigating the mechanisms underlying synaptic assembly, function, and plasticity. We will discuss techniques for studying synapses in Drosophila, with a focus on the larval neuromuscular junction (NMJ), a well-established model glutamatergic synapse. Vesicle fusion, which underlies synaptic release of neurotransmitters, has been well characterized at this synapse. In addition, studies of synaptic assembly and organization of active zones and postsynaptic densities have revealed pathways that coordinate those events across the synaptic cleft. We will also review modes of synaptic growth and plasticity at the fly NMJ, and discuss how pre-and postsynaptic cells communicate to regulate plasticity in response to activity. KEYWORDS FlyBook; Drosophila; synapse; neurotransmitter release; synaptic plasticity; active zone; synaptic vesicle TABLE OF CONTENTS Abstract 345Introduction 345

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“…We used the depolarization-dependent lipophilic FM1-43 dye labeling technique to monitor the synaptic vesicle (SV) cycle, including both SV endocytosis and exocytosis (Betz and Bewick, 1992). Upon depolarization with high K + saline (90 mM), FM1-43 dye is incorporated into vesicles ('loading') during endocytosis, providing a measure of the functional SV cycling pool size (Staples and Broadie, 2013;Vijayakrishnan et al, 2009). A second high K + saline depolarization in the absence of the FM1-43 dye drives vesicle fusion ('unloading') during neurotransmission exocytosis, as a measure of SV release efficacy from presynaptic boutons.…”

Section: Timp Facilitates Synaptic Vesicle Cycling Rate and Functionamentioning

confidence: 99%

“…Wandering third-instar immunolabeling was performed as previously described (Staples and Broadie, 2013 …”

Section: Immunocytochemistrymentioning

confidence: 99%

Secreted tissue inhibitor of matrix metalloproteinase restricts trans-synaptic signaling to coordinate synaptogenesis

Shilts

Broadie

2017

Journal of Cell Science

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Synaptogenesis is coordinated by trans-synaptic signals that traverse the specialized synaptomatrix between presynaptic and postsynaptic cells. Matrix metalloproteinase (Mmp) activity sculpts this environment, balanced by secreted tissue inhibitors of Mmp (Timp). Here, we use the simplified Drosophila melanogaster matrix metalloproteome to test the consequences of eliminating all Timp regulatory control of Mmp activity at the neuromuscular junction (NMJ). Using in situ zymography, we find Timp limits Mmp activity at the NMJ terminal and shapes extracellular proteolytic dynamics surrounding individual synaptic boutons. In newly generated timp null mutants, NMJs exhibit architectural overelaboration with supernumerary synaptic boutons. With cell-targeted RNAi and rescue studies, we find that postsynaptic Timp limits presynaptic architecture. Functionally, timp null mutants exhibit compromised synaptic vesicle cycling, with activity that is lower in amplitude and fidelity. NMJ defects manifest in impaired locomotor function. Mechanistically, we find that Timp limits BMP trans-synaptic signaling and the downstream synapse-to-nucleus signal transduction. Pharmacologically restoring Mmp inhibition in timp null mutants corrects bone morphogenetic protein (BMP) signaling and synaptic properties. Genetically restoring BMP signaling in timp null mutants corrects NMJ structure and motor function. Thus, Timp inhibition of Mmp proteolytic activity restricts BMP trans-synaptic signaling to coordinate synaptogenesis.

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The cell polarity scaffold lethal giant larvae regulates synapse morphology and function

Cited by 10 publications

References 67 publications

N-glycosylation requirements in neuromuscular synaptogenesis

N-glycosylation requirements in neuromuscular synaptogenesis

Transmission, Development, and Plasticity of Synapses

Secreted tissue inhibitor of matrix metalloproteinase restricts trans-synaptic signaling to coordinate synaptogenesis

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