Development and plasticity of the <i>Drosophila</i> larval neuromuscular junction

Menon, Kaushiki P.; Carrillo, Robert A.; Zinn, Kai

doi:10.1002/wdev.108

Cited by 205 publications

(221 citation statements)

References 192 publications

(207 reference statements)

Supporting

Mentioning

215

Contrasting

Order By: Relevance

“…Mmp1 and Mmp2 both regulate synapse molecular assembly NMJ function is regulated by the number and composition of postsynaptic glutamate receptors (GluRs) juxtaposing presynaptic active zone glutamate release sites (Menon et al, 2013). Since both evoked and spontaneous neurotransmission are altered in Mmp mutants, we next tested how the two Mmp classes might regulate molecular synaptic assembly by quantifying both presynaptic Bruchpilot (Brp) containing active zones (Wagh et al, 2006) and postsynaptic GluR domains (Qin et al, 2005).…”

Section: Mmp1 and Mmp2 Both Regulate Differentiation Of Synapse Functionmentioning

confidence: 99%

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

et al. 2015

View full text Add to dashboard Cite

Synaptogenesis requires orchestrated intercellular communication between synaptic partners, with trans-synaptic signals necessarily traversing the extracellular synaptomatrix separating presynaptic and postsynaptic cells. Extracellular matrix metalloproteinases (Mmps) regulated by secreted tissue inhibitors of metalloproteinases (Timps), cleave secreted and membrane-associated targets to sculpt the extracellular environment and modulate intercellular signaling. Here, we test the roles of Mmp at the neuromuscular junction (NMJ) model synapse in the reductionist Drosophila system, which contains just two Mmps (secreted Mmp1 and GPI-anchored Mmp2) and one secreted Timp. We found that all three matrix metalloproteome components co-dependently localize in the synaptomatrix and show that both Mmp1 and Mmp2 independently restrict synapse morphogenesis and functional differentiation. Surprisingly, either dual knockdown or simultaneous inhibition of the two Mmp classes together restores normal synapse development, identifying a reciprocal suppression mechanism. The two Mmp classes coregulate a Wnt trans-synaptic signaling pathway modulating structural and functional synaptogenesis, including the GPIanchored heparan sulfate proteoglycan (HSPG) Wnt co-receptor Dally-like protein (Dlp), cognate receptor Frizzled-2 (Frz2) and Wingless (Wg) ligand. Loss of either Mmp1 or Mmp2 reciprocally misregulates Dlp at the synapse, with normal signaling restored by coremoval of both Mmp classes. Correcting Wnt co-receptor Dlp levels in both Mmp mutants prevents structural and functional synaptogenic defects. Taken together, these results identify an Mmp mechanism that fine-tunes HSPG co-receptor function to modulate Wnt signaling to coordinate synapse structural and functional development.

show abstract

Section: Mmp1 and Mmp2 Both Regulate Differentiation Of Synapse Functionmentioning

confidence: 99%

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Therefore, we hypothesized that Mmp regulation is a major determinant of synaptic architecture. The number of synaptic boutons, where neurotransmission occurs, is a robust measure of synaptic architecture, and is furthermore highly plastic over development and in response to activity-dependent modulation (Menon et al, 2013). At the wandering third-instar stage NMJ, each muscle shows a relatively stereotypical pattern of innervation, with similar branching arbors containing a consistent number of synaptic boutons.…”

Section: Timp Constrains the Pattern Of Mmp Proteolytic Activity At Nmentioning

confidence: 99%

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

Shilts

Broadie

2017

Journal of Cell Science

View full text Add to dashboard Cite

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.

show abstract

“…These synapses are glutamatergic, stereotypically positioned, and resemble mammalian central synapses in terms of the neurotransmitter used [50,51] . Compelling evidence has shown that glia, closely associated with these synapses, modulate synaptic activity and synapse formation [52][53][54][55][56] .…”

Section: Glia-derived Factors During Synapse Formation and Functionmentioning

confidence: 99%

Glial cells in neuronal development: recent advances and insights from Drosophila melanogaster

Xiao

et al. 2014

Neurosci. Bull.

View full text Add to dashboard Cite

Glia outnumber neurons and are the most abundant cell type in the nervous system. Whereas neurons are the major carriers, transducers, and processors of information, glial cells, once considered mainly to play a passive supporting role, are now recognized for their active contributions to almost every aspect of nervous system development. Recently, insights from the invertebrate organism Drosophila melanogaster have advanced our knowledge of glial cell biology. In particular, findings on neuron-glia interactions via intrinsic and extrinsic mechanisms have shed light on the importance of glia during different stages of neuronal development. Here, we summarize recent advances in understanding the functions of Drosophila glia, which resemble their mammalian counterparts in morphology and function, neural stem-cell conversion, synapse formation, and developmental axon pruning. These discoveries reinforce the idea that glia are substantial players in the developing nervous system and further advance the understanding of mechanisms leading to neurodegeneration.Keywords: glia; neuronal development; Gcm; neurodegeneration; neural stem cell; synapse formation; axon pruning Conventionally, glia have been considered to play a passive supporting role due to a lack of electrical excitability for transducing information like neurons. Nonetheless, compelling evidence has demonstrated that glia participate actively in mediating a number of neuronal events such as axon guidance, peripheral axon ensheathment, and formation of the blood-brain barrier to protect the central nervous system (CNS) [1][2][3][4][5] . On the other hand, a tripartite model that includes glia has recently been proposed to revise the classical view of synaptic structure [6][7][8] . In addition to the presynaptic and postsynaptic compartments, adjacent glia, particularly mammalian astrocytes, are now envisioned as one of the major components integrating synaptic function by releasing gliotransmitters, promoting synapse formation, and regulating synaptic plasticity [9] .Intriguingly, studies from the invertebrate model organism Several recent articles have provided excellent overviews of the origin and development of glia [10][11][12][13][14] . In this review, we explicitly summarize glial functions that have emerged as key mechanisms in the regulation of neuronal development in Drosophila. We describe the distinct classes of Drosophila glia, followed by a discussion of how they modulate neural stem-cell behavior, an extrinsic regulatory step during the early stage of neural fate decision. Next, we discuss how glia secrete different factors to affect the development and function of the neuromuscular junction (NMJ). Finally, we compare the glia-derived two-step secretion/engulfment mechanism in NMJ remodeling with axon pruning of mushroom body (MB) γ-neurons.Altogether, these recent discoveries point to a significant role for glia during neuronal development, and provide novel insights into mechanisms leading to a destabilized state of the nervous system, as i...

show abstract

Development and plasticity of the Drosophila larval neuromuscular junction

Cited by 205 publications

References 192 publications

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

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

Glial cells in neuronal development: recent advances and insights from Drosophila melanogaster

Contact Info

Product

Resources

About