A novel Netrin-1–sensitive mechanism promotes local SNARE-mediated exocytosis during axon branching

Winkle, Cortney C.; McClain, Leslie Marie; Valtschanoff, Juli G.; Park, Charles S.; Christopher, Maglione,; Gupton, Stephanie L.

doi:10.1083/jcb.201311003

Cited by 86 publications

(260 citation statements)

References 72 publications

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“…2A), which is in agreement with earlier studies where low concentrations of Netrin-1 has been shown not to affect axon velocity. 8,33,42 Axons treated with 0.5 µg/ml Netrin-1 had a significantly different velocity distribution compared to control group (p < 0.05) and the difference in the velocity distribution became more significant with increasing Netrin-1 concentrations (p < 0.001). The velocity distribution in axons treated with 1.0 and 2.5 µg/ml Netrin-1 were similar to each other suggesting that the response reaches its peak around 1.0 µg/ml and remains constant with increasing Netrin-1 concentration.…”

Section: Resultsmentioning

confidence: 88%

Neuron Subpopulations with Different Elongation Rates and DCC Dynamics Exhibit Distinct Responses to Isolated Netrin-1 Treatment

Blasiak

Kilinc

2015

ACS Chem. Neurosci.

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Correct wiring of the nervous system requires guidance cues, diffusible or substrate-bound proteins that steer elongating axons to their target tissues. Netrin-1, the best characterized member of the Netrins family of guidance molecules, is known to induce axon turning and modulate axon elongation rate; however, the factors regulating the axonal response to Netrin-1 are not fully understood. Using microfluidics, we treated fluidically-isolated axons of mouse primary cortical neurons with Netrin-1 and characterized axon elongation rates, as well as the membrane localization of deleted in colorectal cancer (DCC), a well-established receptor of Netrin-1. The capacity to stimulate and observe a large number of individual axons allowed us to conduct distribution analyses, through which we identified two distinct neuron sub-populations based on different elongation behavior and different DCC membrane dynamics. Netrin-1 reduced the elongation rates in both sub-populations, where the effect was more pronounced in the slow growing sub-population. Both the source of Ca 2+ influx and the basal cytosolic Ca 2+ levels regulated the effect of Netrin-1, e.g., Ca 2+ efflux from the endoplasmic reticulum due to the activation of Ryanodine channels blocked Netrin-1-induced axon slowdown. Netrin-1 treatment resulted in a rapid membrane insertion of DCC, followed by a gradual internalization. DCC membrane dynamics were different in the central regions of the growth cones compared to filopodia and axon shafts, highlighting the temporal and spatial heterogeneity in the signaling events downstream of Netrin-1. Cumulatively, these results demonstrate the power of microfluidic compartmentalization and distribution analysis in describing the complex axonal Netrin-1 response.

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Section: Resultsmentioning

confidence: 88%

Neuron Subpopulations with Different Elongation Rates and DCC Dynamics Exhibit Distinct Responses to Isolated Netrin-1 Treatment

Blasiak

Kilinc

2015

ACS Chem. Neurosci.

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“…Timed pregnant females were obtained by placing male and female mice together overnight; the following day was designated as E0.5 if the female had a vaginal plug. Trim9 Ϫ/Ϫ , Trim9 fl/fl , and Thy1-GFP mice were described (Feng et al, 2000;Winkle et al, 2014). A Nex-Cre line (from Dr. Klaus Nave) (Goebbels et al, 2006) and a Tau loxP-stop-loxP GFP line (from Dr. Eva Anton) (Higginbotham et al, 2012) were crossed with Trim9 fl/fl mice.…”

Section: Methodsmentioning

confidence: 99%

“…Deletion of Trim9 in cortical neurons is associated with elevated exocytosis, increased stability of growth cone filopodia, and loss of netrin responsiveness in vitro. These phenotypes are associated with aberrant branching and projection of cortical axons both in vitro and in vivo (Winkle et al, 2014;Menon et al, 2015), suggesting that TRIM9 regulates membrane delivery and cytoskeletal dynamics powering cortical neuron morphogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…We recently identified TRIM9 as a regulator of neuronal morphogenesis in cortical neurons (Winkle et al, 2014;Menon et al, 2015). TRIM9 directly interacts with exocytic t-SNARE SNAP25 (Li et al, 2001), the actin polymerase VASP (Menon et al, 2015), and DCC, a receptor for the axon guidance cue netrin (Winkle et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Neuronal processes ramify to innervate multiple synaptic partners, and synapses change size and shape in response to extracellular signals and neural activity (Song et al, 2015). Appropriate morphogenesis requires regulated cytoskeletal dynamics to provide protrusive force to alter cell shape and delivery of materials for plasma membrane expansion (Pfenninger, 2009;Gupton and Gertler, 2010;Dent et al, 2011;Menon and Gupton, 2016;Winkle and Gupton, 2016).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Trim9Deletion Alters the Morphogenesis of Developing and Adult-Born Hippocampal Neurons and Impairs Spatial Learning and Memory

et al. 2016

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During hippocampal development, newly born neurons migrate to appropriate destinations, extend axons, and ramify dendritic arbors to establish functional circuitry. These developmental stages are recapitulated in the dentate gyrus of the adult hippocampus, where neurons are continuously generated and subsequently incorporate into existing, local circuitry. Here we demonstrate that the E3 ubiquitin ligase TRIM9 regulates these developmental stages in embryonic and adult-born mouse hippocampal neurons in vitro and in vivo. Embryonic hippocampal and adult-born dentate granule neurons lacking Trim9 exhibit several morphological defects, including excessive dendritic arborization. Although gross anatomy of the hippocampus was not detectably altered by Trim9 deletion, a significant number of Trim9 Ϫ/Ϫ adult-born dentate neurons localized inappropriately. These morphological and localization defects of hippocampal neurons in Trim9 Ϫ/Ϫ mice were associated with extreme deficits in spatial learning and memory, suggesting that TRIM9-directed neuronal morphogenesis may be involved in hippocampal-dependent behaviors.

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Detection of High‐Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins

Bartley,

Ngo,

et al. 2023

Annals of Neurology

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Co‐occurring anti‐tripartite motif‐containing protein 9 and 67 autoantibodies (TRIM9/67‐IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67‐IgG detection are not known. We performed a retrospective, multi‐center study to evaluate the cerebrospinal fluid (CSF) and serum of candidate TRIM9/67‐IgG cases by tissue‐based immunofluorescence (TBIF), peptide phage display immunoprecipitation sequencing (PhIP‐Seq), overexpression cell‐based assay (CBA), and immunoblot. Cases in whom TRIM9/67‐IgG was detected by at least two assays were considered TRIM9/67‐IgG positive. Among these cases (N=13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67‐IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (N = 7/10), followed by encephalitis (N = 3/10). Of these ten, 70% had comorbid cancer (7/10), 85% of whom (N = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (N = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. TRIM9/67‐IgG are rare but likely high‐risk paraneoplastic biomarkers for which CBA appears to be the most sensitive diagnostic assay.This article is protected by copyright. All rights reserved.

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A novel Netrin-1–sensitive mechanism promotes local SNARE-mediated exocytosis during axon branching

Abstract: Localized plasma membrane expansion during axon branching mediated by Netrin-1 occurs via TRIM9-dependent regulation of SNARE-mediated vesicle fusion.

Cited by 86 publications

References 72 publications

Neuron Subpopulations with Different Elongation Rates and DCC Dynamics Exhibit Distinct Responses to Isolated Netrin-1 Treatment

Neuron Subpopulations with Different Elongation Rates and DCC Dynamics Exhibit Distinct Responses to Isolated Netrin-1 Treatment

Trim9Deletion Alters the Morphogenesis of Developing and Adult-Born Hippocampal Neurons and Impairs Spatial Learning and Memory

Detection of High‐Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins

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