Transsynaptic Signaling by Activity-Dependent Cleavage of Neuroligin-1

Peixoto, Rui T.; Kunz, Portia A.; Kwon, Hyung-Bae; Mabb, Angela M.; Sabatini, Bernardo L.; Philpot, Benjamin D.; Ehlers, Michael

doi:10.1016/j.neuron.2012.07.006

Cited by 203 publications

(249 citation statements)

References 51 publications

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“…This indicated MMP and ADAM family proteases as candidate enzymes, a prediction consistent with the reported enzyme(s) responsible for Nlgn1 cleavage 17,18 and neural ADAM10 targets 19 . Active slice CM generated in the absence and presence of various protease inhibitors exhibited decreased neuroligin-3 shedding with MMP9 and ADAM10 inhibitors (Fig.…”

supporting

confidence: 85%

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Venkatesh

Tam

Woo

et al. 2017

Nature

371

374

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Summary High-grade gliomas (HGG) are a devastating group of cancers, representing the leading cause of brain tumor-related death in both children and adults. Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway1. However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified. Here, we demonstrate a striking dependence of HGG growth on microenvironmental neuroligin-3, elucidate signaling cascades downstream of neuroligin-3 binding in glioma and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. Neuroligin-3 stimulates numerous oncogenic pathways, including early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes including upregulation of numerous synapse-related genes in glioma cells. Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent release of neuroligin-3 into the tumor microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting neuroligin-3 secretion, which could prove transformative for HGG therapy.

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supporting

confidence: 85%

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Venkatesh

Tam

Woo

et al. 2017

Nature

371

374

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“…They found that only MMP-9, neither MMP-2 nor MMP-3, was involved in Ca 2þ /calmodulin-dependent protein kinase signaling pathway. 31 For in vivo studies, using the same ischemic mouse models, we previously observed during the course of experiments that MMP-9 levels were dramatically unregulated and activated while MMP-2 levels remained similar in the ischemic cortex and the non-lesioned cortex, suggesting that MMP-9 is the predominant gelatinase involved, at least under our experimental conditions. 8,20,21,32 Our observations are consistent with the studies of Lo and others, [33][34][35] suggesting that there is only low level induction of MMP-2 after cerebral ischemia in rodent models; moreover, these levels of MMP-2 are much lower than those of MMP-9.…”

Section: Discussionsupporting

confidence: 55%

Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke

Chen

Cui

Jiang

et al. 2016

J Cereb Blood Flow Metab

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Matrix metalloproteinases (MMPs), particularly gelatinases (MMP-2/-9), are involved in neurovascular impairment after stroke. Detection of gelatinase activity in vivo can provide insight into blood-brain barrier disruption, hemorrhage, and nerve cell injury or death. We applied gelatinase-activatable cell-penetrating peptides (ACPP) with a cleavable L-amino acid linker to examine gelatinase activity in primary neurons in culture and ischemic mouse brain in vivo. We found uptake of Cy5-conjugated ACPP (ACPP-Cy5) due to gelatinase activation both in cultured neurons exposed to N-methyl-D-aspartate and in mice after cerebral ischemia. Fluorescence intensity was significantly reduced when cells or mice were treated with MMP inhibitors or when a cleavage-resistant ACPP-Cy5 was substituted. We also applied an ACPP dendrimer (ACPPD) conjugated with multiple Cy5 and/or gadolinium moieties for fluorescence and magnetic resonance imaging (MRI) in intact animals. Fluorescence analysis showed that ACPPD was detected in subfemtomole range in ischemic tissues. Moreover, MRI and inductively coupled plasma mass spectrometry revealed that ACPPD produced quantitative measures of gelatinase activity in the ischemic region. The resulting spatial pattern of gelatinase activity and neurodegeneration were very similar. We conclude that ACPPs are capable of tracing spatiotemporal gelatinase activity in vivo, and will therefore be useful in elucidating mechanisms of gelatinase-mediated neurodegeneration after stroke.

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“…In addition, it could facilitate synaptic disassembly. For example, removal of transsynaptic ligands by proteolytic cleavage, as recently reported for neuroligin-1 (Peixoto et al, 2012;Suzuki et al, 2012) and NGL-3 , might rapidly reduce the affinity of cis interactions and trigger the disassembly of adhesion protein complexes.…”

Section: Discussionmentioning

confidence: 88%

Trans-induced cis interaction in the tripartite NGL-1, netrin-G1, and LAR adhesion complex promotes excitatory synaptic development

Song

Lee

Prosselkov

et al. 2013

Journal of Cell Science

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SummaryThe initial contact between axons and dendrites at early neuronal synapses is mediated by surface adhesion molecules and is thought to induce synaptic maturation through the recruitment of additional synaptic proteins. The initiation of synaptic maturation should be tightly regulated to ensure that synaptic maturation occurs selectively at subcellular sites of axo-dendritic adhesion. However, the underlying mechanism is poorly understood. Here, we report that the initial trans-synaptic adhesion mediated by presynaptic netrin-G1 and postsynaptic NGL-1 (netrin-G1 ligand-1) induces a cis interaction between netrin-G1 and the receptor protein tyrosine phosphatase LAR (leukocyte antigen-related), and that this promotes presynaptic differentiation. We propose that trans-synaptic adhesions at early neuronal synapses trigger recruitment of neighboring adhesion molecules in a cis manner in order to couple initial axo-dendritic adhesion with synaptic differentiation.

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Transsynaptic Signaling by Activity-Dependent Cleavage of Neuroligin-1

Cited by 203 publications

References 51 publications

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke

Trans-induced cis interaction in the tripartite NGL-1, netrin-G1, and LAR adhesion complex promotes excitatory synaptic development

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