Semaphorin 4A induces growth cone collapse of hippocampal neurons in a Rho/Rho-kinase-dependent manner

Yukawa, Kazunori; Tanaka, Tetsuji; Bai, Tong; Umemura, Takashi; Owada-Makabe, Kyoko; Tsubota, Yuji; Maeda, Masanobu; Suzuki, Kazuhiro; Kikutani, Hitoshi; Kumanogoh, Atsushi

doi:10.3892/ijmm.16.1.115

Cited by 24 publications

(22 citation statements)

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“…Moreover, in the presence of the Rho family GTPase Rnd1, the binding of Sema4A to PlexinB1-B2 and B3 induces COS7 cell contraction through the R-Ras GTPase-activating protein enzymatic activity that characterizes all Plexin cytodomains studied so far (21). Besides acting as a chemorepulsive cue via B-type plexins (21,22), Sema4A has been shown to be constitutively expressed by dendritic cells, where it stimulates T cell activation through Tim-2 receptor, a member of the T cell Ig and mucine domain proteins expressed on activated T cells (19). Moreover, T cells require Sema4A to allow Th cell differentiation.…”

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confidence: 99%

Semaphorin 4A Exerts a Proangiogenic Effect by Enhancing Vascular Endothelial Growth Factor-A Expression in Macrophages

Meda

Molla

Pizzol

et al. 2012

The Journal of Immunology

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The axon guidance cues semaphorins (Semas) and their receptors plexins have been shown to regulate both physiological and pathological angiogenesis. Sema4A plays an important role in the immune system by inducing T cell activation, but to date, the role of Sema4A in regulating the function of macrophages during the angiogenic and inflammatory processes remains unclear. In this study, we show that macrophage activation by TLR ligands LPS and polyinosinic-polycytidylic acid induced a time-dependent increase of Sema4A and its receptors PlexinB2 and PlexinD1. Moreover, in a thioglycollate-induced peritonitis mouse model, Sema4A was detected in circulating Ly6Chigh inflammatory monocytes and peritoneal macrophages. Acting via PlexinD1, exogenous Sema4A strongly increased macrophage migration. Of note, Sema4A-activated PlexinD1 enhanced the expression of vascular endothelial growth factor-A, but not of inflammatory chemokines. Sema4A-stimulated macrophages were able to activate vascular endothelial growth factor receptor-2 and the PI3K/serine/threonine kinase Akt pathway in endothelial cells and to sustain their migration and in vivo angiogenesis. Remarkably, in an in vivo cardiac ischemia/reperfusion mouse model, Sema4A was highly expressed in macrophages recruited at the injured area. We conclude that Sema4A activates a specialized and restricted genetic program in macrophages able to sustain angiogenesis and participates in their recruitment and activation in inflammatory injuries.

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confidence: 99%

Semaphorin 4A Exerts a Proangiogenic Effect by Enhancing Vascular Endothelial Growth Factor-A Expression in Macrophages

Meda

Molla

Pizzol

et al. 2012

The Journal of Immunology

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“…Sema4A expressed in dendritic cells and B-cells enhances the activation of T-cells and the generation of antigenspecific T-cells by virtue of the interaction with the Sema4A receptor, Tim-2, a member of the T-cell immunoglobulin domain and mucin domain (Tim) proteins expressed on activated T-cells (12). Our previous study showed that recombinant Sema4A induces growth cone collapse in mouse hippocampal neurons (13). The binding of Sema4A to the growth cones indicated the presence of a specific receptor transmitting Sema4A signal via the intracellular effectors to induce growth cone collapse in the neurons (13).…”

Section: Introductionmentioning

confidence: 99%

“…Our previous study showed that recombinant Sema4A induces growth cone collapse in mouse hippocampal neurons (13). The binding of Sema4A to the growth cones indicated the presence of a specific receptor transmitting Sema4A signal via the intracellular effectors to induce growth cone collapse in the neurons (13). In the current study, to identify the functional Sema4A receptor and the signal transduction machinery, we first performed COS-7 cell contraction assay, in which Sema4A-induced intracellular signaling triggered cell contraction (14).…”

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confidence: 99%

Sema4A induces cell morphological changes through B-type plexin-mediated signaling

Yukawa

Tanaka²,

Yoshida³

et al. 2009

Int J Mol Med

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Abstract. Semaphorins are a family of secreted and membranebound proteins known as axonal pathfinders. Sema4A, a member of class 4 semaphorins, induces growth cone collapse of hippocampal neurons. The binding of Sema4A to growth cones indicates the presence of receptors transmitting signals through the intracellular effectors to induce growth cone collapse in hippocampal neurons. Transfection experiments of the candidate receptor genes into COS-7 cells demonstrated that Sema4A binds to axonal guidance receptors Plexin-B1, -B2 and -B3. To identify the functional Sema4A receptor and the signal transduction machinery, COS-7 cell contraction assay was performed, in which intracellular signal transmission induced by Sema4A triggered cell contraction. Expression vectors encoding plexins and Rnd1, a Rho family GTPase, were transfected into COS-7 cells, and a proportion of contracted cells among the transfectants was determined after incubation with Sema4A. The results demonstrated that the combination of Rnd1 and Plexin-B1, -B2 or -B3 induced significant cell contraction, indicating that B-type plexins transmit an intracellular signal of Sema4A through Rnd1. To further study the mechanism of B-type plexin-mediated signaling in Sema4A-induced growth cone collapse, mouse hippocampal neurons transfected with a control or expression plasmid encoding a constitutively active mutant of R-Ras (R-RasQL) were stimulated with Sema4A, followed by the assessment of growth cone collapse. Expression of R-RasQL significantly blocked Sema4A-induced growth cone collapse in the hippocampal neurons compared with the control plasmid. Sema4A thus induces growth cone collapse through the down-regulation of R-Ras activity in mouse hippocampal neurons.

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“…For instance, via plexin D1, SEMA4A inhibits endothelial cell migration and in vivo angiogenesis by suppressing vascular endothelial growth factor-mediated activation of Rac and integrin-dependent cell adhesion (17). In the presence of the Rho family GTPase Rnd1, the binding of SEMA4A to plexin Bs induces cellular contraction through enzymatic activity of R-Ras, a GTPase-activating protein (35,36).…”

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mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells

Ito

Nojima

Nishide

et al. 2015

The Journal of Immunology

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Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of mTOR-mediated signals in CD4+ T cell responses, the involvement of mTOR in CD8+ T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8+ T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A−/− CD8+ T cells exhibited impairments in production of IFN-γ and TNF-α and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen-specific effector CD8+ T cell responses were significantly impaired in SEMA4A−/− mice. Furthermore, SEMA4A−/− CD8+ T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8+ T cells. IFN-γ production and mTORC1 activity in SEMA4A−/− CD8+ T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8+ T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8+ T cells, but also reveal a novel link between a semaphorin and mTOR signaling.

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Semaphorin 4A induces growth cone collapse of hippocampal neurons in a Rho/Rho-kinase-dependent manner

Cited by 24 publications

References 0 publications

Semaphorin 4A Exerts a Proangiogenic Effect by Enhancing Vascular Endothelial Growth Factor-A Expression in Macrophages

Semaphorin 4A Exerts a Proangiogenic Effect by Enhancing Vascular Endothelial Growth Factor-A Expression in Macrophages

Sema4A induces cell morphological changes through B-type plexin-mediated signaling

mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells

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