Postsynaptic Mad Signaling at the Drosophila Neuromuscular Junction

Dudu, Veronica; Bittig, Thomas; Entchev, Eugeni V.; Kicheva, Anna; Jülicher, Frank; González‐Gaitán, Marcos

doi:10.1016/j.cub.2006.02.061

Cited by 56 publications

(50 citation statements)

References 38 publications

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“…We next tested whether activity regulates the abundance of synaptic Mmps using both genetic and ionic stimulation paradigms (64, 65, 71, 72). We labeled Mmp1 with well-characterized antibodies, using detergent-free conditions to mark extracellular protein (7, 21, 73–75).…”

Section: Resultsmentioning

confidence: 99%

Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis

2017

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Matrix metalloproteinase (MMP) functions modulate synapse formation and activity-dependent plasticity, with MMP dysfunction implicated in Fragile X syndrome (FXS), a disease caused by the loss of the RNA binding protein FMRP and characterized by neurological dysfunction and intellectual disability. Gene expression studies in Drosophila suggest that Mmps cooperate with the heparan sulfate proteoglycan (HSPG) glypican co-receptor Dally-like protein (Dlp) to restrict trans-synaptic Wnt signaling, and that synaptogenic defects in the fly model of FXS are alleviated by both Mmp inhibition and Dlp genetic reduction. Here, we used the Drosophila neuromuscular junction (NMJ) glutamatergic synapse to test activity-dependent Dlp and Mmp intersections in the context of FXS. We found that rapid, activity-dependent synaptic bouton formation was dependent upon secreted Mmp1. Acute neuronal stimulation reduced Mmp2 abundance, but increased that of both Mmp1 and Dlp as well as Dlp and Mmp1 co-localization at the synapse. Dlp function bidirectionally controlled Mmp1 abundance, localization and proteolytic activity around synapses. Dlp glycosaminoglycan (GAG) chains mediated this functional interaction with Mmp1. In the FXS fly model, activity-dependent increases in Mmp1 abundance and activity were lost but were restored by reducing the amount of synaptic Dlp. These data indicate that neuronal activity-induced, HSPG-dependent Mmp regulation drives activity-dependent synaptogenesis, and that this is impaired in FXS. Thus exploring this mechanism further may reveal therapeutic targets with potential to restore synaptogenesis in FXS patients.

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Section: Resultsmentioning

confidence: 99%

Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis

2017

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“…Our data do not exclude the possibility that motoneuron-derived Gbb induces a postsynaptic signal that in turn promotes neurotransmitter release. Given the number and complexity of signaling interactions at the NMJ (Dudu et al, 2006; Fuentes-Medel et al, 2012; Korkut et al, 2013), it will be crucial to test if components of the BMP signal transduction machinery display postsynaptic requirements for neurotransmitter release.…”

Section: Discussionmentioning

confidence: 99%

Crimpy Enables Discrimination of Presynaptic and Postsynaptic Pools of a BMP at the Drosophila Neuromuscular Junction

et al. 2014

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Summary Distinct pools of the BMP Glass bottom boat (Gbb) control structure and function of the Drosophila neuromuscular junction. Specifically, motoneuron-derived Gbb regulates baseline neurotransmitter release, while muscle-derived Gbb regulates NMJ growth. Yet how cells differentiate between these ligand pools is not known. Here we present evidence that the neuronal Gbb-binding protein Crimpy (Cmpy) permits discrimination of pre and postsynaptic ligand by serving sequential functions in Gbb signaling. Cmpy first delivers Gbb to dense core vesicles (DCVs) for activity-dependent release from presynaptic terminals. In the absence of Cmpy, Gbb is no longer associated with DCVs and is not released by activity. Electrophysiological analyses demonstrate that Cmpy promotes Gbb's pro-neurotransmission function. Surprisingly, the Cmpy ectodomain is itself released upon DCV exocytosis, arguing that Cmpy serves a second function in BMP signaling. In addition to trafficking Gbb to DCVs, we propose that Gbb/Cmpy co-release from presynaptic terminals defines a neuronal pro-transmission signal.

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“…The following primary antibodies were used: FITC-conjugated anti-HRP (1:250, Jackson ImmunoResearch laboratories), rabbit anti-Tkv (1:500, Dudu et al 2006), rabbit anti-PS1 (p-Mad) (1:500; a gift from P. ten Dijke), guinea pig anti-Dnrx (1:250, Li et al, 2007), and guinea pig anti-Dnlg1 (1:250, Mozer and Sandstorm, 2012). Mouse monoclonal anti-Dlg (1:500, 4F3), anti-BRP (1:250; NC82) and anti-Wit (1:25, 23C7) were obtained from Developmental Studies Hybridoma Bank (DSHB), University of Iowa.…”

Section: Methodsmentioning

confidence: 99%

Neurexin, Neuroligin and Wishful Thinking coordinate synaptic cytoarchitecture and growth at neuromuscular junctions

Banerjee

Venkatesan

Bhat

2017

Molecular and Cellular Neuroscience

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Trans-synaptic interactions involving Neurexins and Neuroligins are thought to promote adhesive interactions for precise alignment of the pre- and postsynaptic compartments and organize synaptic macromolecular complexes across species. In Drosophila, while Neurexin (Dnrx) and Neuroligins (Dnlg) are emerging as central organizing molecules at synapses, very little is known of the spectrum of proteins that might be recruited to the Dnrx/Dnlg trans-synaptic interface for organization and growth of the synapses. Using full length and truncated forms of Dnrx and Dnlg1 together with cell biological analyses and genetic interactions, we report novel functions of Dnrx and Dnlg1 in clustering of pre- and postsynaptic proteins, coordination of synaptic growth and ultrastructural organization. We show that Dnrx and Dnlg1 extracellular and intracellular regions are required for proper synaptic growth and localization of Dnlg1 and Dnrx, respectively. dnrx and dnlg1 single and double mutants display altered subcellular distribution of Discs large (Dlg), which is the homolog of mammalian post-synaptic density protein, PSD95. dnrx and dnlg1 mutants also display ultrastructural defects ranging from abnormal active zones, misformed pre- and post-synaptic areas with underdeveloped subsynaptic reticulum. Interestingly, dnrx and dnlg1 mutants have reduced levels of the BMP receptor Wishful thinking (Wit), and Dnrx and Dnlg1 are required for proper localization and stability of Wit. In addition, the synaptic overgrowth phenotype resulting from the overexpression of Dnrx fails to manifest in wit mutants. Phenotypic analyses of dnrx/wit and dnlg1/wit mutants indicate that Dnrx/Dnlg1/Wit coordinate synaptic growth and architecture at the NMJ. Our findings also demonstrate that loss of Dnrx and Dnlg1 leads to decreased levels of the BMP co-receptor, Thickveins and the downstream effector phosphorylated Mad at the NMJ synapses indicating that Dnrx/Dnlg1 regulate components of the BMP signaling pathway. Together our findings reveal that Dnrx/Dnlg are at the core of a highly orchestrated process that combines adhesive and signaling mechanisms to ensure proper synaptic organization and growth during NMJ development.

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Postsynaptic Mad Signaling at the Drosophila Neuromuscular Junction

Abstract: Our data suggest a mechanism linking synaptic transmission and postsynaptic TGF-beta signaling that may coordinate nerve-muscle development and function.

Cited by 56 publications

References 38 publications

Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis

Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis

Crimpy Enables Discrimination of Presynaptic and Postsynaptic Pools of a BMP at the Drosophila Neuromuscular Junction

Neurexin, Neuroligin and Wishful Thinking coordinate synaptic cytoarchitecture and growth at neuromuscular junctions

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