<i>C. elegans</i> Tensin Promotes Axon Regeneration by Linking the Met-like SVH-2 and Integrin Signaling Pathways

Hisamoto, Naoki; Shimizu, Tatsuhiro; Asai, Kazuma; Sakai, Yoshiki; Pastuhov, Strahil Iv.; Hanafusa, Hiroshi; Matsumoto, Kunihiro

doi:10.1523/jneurosci.2059-18.2019

Cited by 13 publications

(13 citation statements)

References 36 publications

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“…We sought to determine whether integrin functions upstream of the RHO-1 pathway in axon regeneration. We have previously reported that PAT-3/integrin β is involved in axonal regeneration ( Hisamoto et al, 2019 ). Here, we first confirmed the pat-3 mutant phenotype.…”

Section: Resultsmentioning

confidence: 99%

“…In the mammalian nervous system, integrins are involved in axon growth, synaptogenesis, and axon regeneration ( Nikonenko et al, 2003 ; Eva and Fawcett, 2014 ). The C. elegans integrins INA-1/integrin α and PAT-3/integrin β also participate in axon regeneration ( Pastuhov et al, 2016 ; Hisamoto et al, 2019 ). In this study, we investigated the relationship between integrin signaling and RhoA activation in the regulation of axon regeneration in C. elegans .…”

Section: Introductionmentioning

confidence: 99%

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The Integrin Signaling Network Promotes Axon Regeneration via the Src–Ephexin–RhoA GTPase Signaling Axis

et al. 2021

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Axon regeneration is an evolutionarily conserved process essential for restoring the function of damaged neurons. In Caenorhabditis elegans hermaphrodites, initiation of axon regeneration is regulated by the RhoA GTPase–ROCK (Rho-associated coiled-coil kinase)–regulatory nonmuscle myosin light-chain phosphorylation signaling pathway. However, the upstream mechanism that activates the RhoA pathway remains unknown. Here, we show that axon injury activates TLN-1/talin via the cAMP–Epac (exchange protein directly activated by cAMP)–Rap GTPase cascade and that TLN-1 induces multiple downstream events, one of which is integrin inside-out activation, leading to the activation of the RhoA–ROCK signaling pathway. We found that the nonreceptor tyrosine kinase Src, a key mediator of integrin signaling, activates the Rho guanine nucleotide exchange factor EPHX-1/ephexin by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the C. elegans integrin signaling network regulates axon regeneration via the Src–RhoGEF–RhoA axis. SIGNIFICANCE STATEMENT The ability of axons to regenerate after injury is governed by cell-intrinsic regeneration pathways. We have previously demonstrated that the Caenorhabditis elegans RhoA GTPase–ROCK (Rho-associated coiled-coil kinase) pathway promotes axon regeneration by inducing MLC-4 phosphorylation. In this study, we found that axon injury activates TLN-1/talin through the cAMP–Epac (exchange protein directly activated by cAMP)–Rap GTPase cascade, leading to integrin inside-out activation, which promotes axonal regeneration by activating the RhoA signaling pathway. In this pathway, SRC-1/Src acts downstream of integrin activation and subsequently activates EPHX-1/ephexin RhoGEF by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the C. elegans integrin signaling network regulates axon regeneration via the Src–RhoGEF–RhoA axis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Integrin Signaling Network Promotes Axon Regeneration via the Src–Ephexin–RhoA GTPase Signaling Axis

et al. 2021

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“…MAPK/ERK and PI3K/Akt signaling pathways can regulate protuberant 15 15 15 15 14 14 13 12 13 12 13 12 11 11 9 8 6 2 growth and protein synthesis related to neural plasticity, and it can assist in the normal development of nerve cells, which may protect against SCZ [22]. e initiation of nerve axon regeneration is regulated by the MAPK pathway and this initiates a neuronal response [23]. Further studies should explore directly whether the CDMGs in the present study are associated with SCZ.…”

Section: Discussionmentioning

confidence: 99%

A Novel Schizophrenia Diagnostic Model Based on Statistically Significant Changes in Gene Methylation in Specific Brain Regions

Zou

Qiu

et al. 2020

BioMed Research International

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Objective. The present study identified methylation patterns of schizophrenia- (SCZ-) related genes in different brain regions and used them to construct a novel DNA methylation-based SCZ diagnostic model. Methods. Four DNA methylation datasets representing different brain regions were downloaded from the Gene Expression Omnibus. The common differentially methylated genes (CDMGs) in all datasets were identified to perform functional enrichment analysis. The differential methylation sites of 10 CDMGs involved in the largest numbers of neurological or psychiatric-related biological processes were used to construct a DNA methylation-based diagnostic model for SCZ in the respective datasets. Results. A total of 849 CDMGs were identified in the four datasets, but the methylation sites as well as degree of methylation differed across the brain regions. Functional enrichment analysis showed CDMGs were significantly involved in biological processes associated with neuronal axon development, intercellular adhesion, and cell morphology changes and, specifically, in PI3K-Akt, AMPK, and MAPK signaling pathways. Four DNA methylation-based classifiers for diagnosing SCZ were constructed in the four datasets, respectively. The sample recognition efficiency of the classifiers showed an area under the receiver operating characteristic curve of 1.00 in three datasets and >0.9 in one dataset. Conclusion. DNA methylation patterns in SCZ vary across different brain regions, which may be a useful epigenetic characteristic for diagnosing SCZ. Our novel model based on SCZ-gene methylation shows promising diagnostic power.

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“…Protein extraction from worms and immunoprecipitation were carried out as described previously (Hisamoto et al 2019). For PNGase treatment, the bead pellets were further washed with wash buffer (20 mM Tris-HCl, pH 7.5, 50 mM NaCl, 5 mM EDTA) for several times and then treated with Rapid PNGase F (New England Biolabs) according to the instruction manual.…”

Section: Methodsmentioning

confidence: 99%

N-Glycosylation of the Discoidin Domain Receptor Is Required for Axon Regeneration in Caenorhabditis elegans

Shimizu

Kato

Sakai³

et al. 2019

Genetics

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Axon regeneration following neuronal injury is an important repair mechanism that is not well understood at present. In Caenorhabditis elegans, axon regeneration is regulated by DDR-2, a receptor tyrosine kinase (RTK) that contains a discoidin domain and modulates the Met-like SVH-2 RTK–JNK MAP kinase signaling pathway. Here, we describe the svh-10/sqv-3 and svh-11 genes, which encode components of a conserved glycosylation pathway, and show that they modulate axon regeneration in C. elegans. Overexpression of svh-2, but not of ddr-2, can suppress the axon regeneration defect observed in svh-11 mutants, suggesting that SVH-11 functions between DDR-2 and SVH-2 in this glycosylation pathway. Furthermore, we found that DDR-2 is N-glycosylated at the Asn-141 residue located in its discoidin domain, and mutation of this residue caused an axon regeneration defect. These findings indicate that N-linked glycosylation plays an important role in axon regeneration in C. elegans.

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C. elegans Tensin Promotes Axon Regeneration by Linking the Met-like SVH-2 and Integrin Signaling Pathways

Cited by 13 publications

References 36 publications

The Integrin Signaling Network Promotes Axon Regeneration via the Src–Ephexin–RhoA GTPase Signaling Axis

The Integrin Signaling Network Promotes Axon Regeneration via the Src–Ephexin–RhoA GTPase Signaling Axis

A Novel Schizophrenia Diagnostic Model Based on Statistically Significant Changes in Gene Methylation in Specific Brain Regions

N-Glycosylation of the Discoidin Domain Receptor Is Required for Axon Regeneration in Caenorhabditis elegans

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