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Critical roles for EphB and ephrin-B bidirectional signalling in retinocollicular mapping.

ABSTRACT: Graded expression of EphB and ephrin-B along the dorsoventral axis of the retina indicates a role for these bidirectional signalling molecules in dorsoventral-mediolateral retinocollicular mapping. Although previous studies have implicated EphB2 forward signalling in mice, the intracellular component of EphB2 essential for retinocollicular mapping is unknown as are the roles for EphB1, ephrin-B1, and ephrin-B2. Here we show that EphB2 tyrosine kinase catalytic activity and EphB1 intracellular signalling are key mediators of ventral-temporal retinal ganglion cell axon retinocollicular mapping, by likely interacting with ephrin-B1 in the superior colliculus. We further elucidate roles for the ephrin-B2 intracellular domain in retinocollicular mapping and present the unexpected finding that both dorsal and ventral-temporal retinal ganglion cell axons utilize reverse signalling for topographic mapping. These data demonstrate that both forward and reverse signalling initiated by EphB:ephrin-B interactions have a major role in dorsoventral retinal ganglion cell axon termination along the mediolateral axis of the superior colliculus.

SUBMITTER: Thakar S

PROVIDER: S-EPMC3518405 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Critical roles for EphB and ephrin-B bidirectional signalling in retinocollicular mapping.

Thakar Sonal S Chenaux George G Henkemeyer Mark M

Nature communications 20110816

Graded expression of EphB and ephrin-B along the dorsoventral axis of the retina indicates a role for these bidirectional signalling molecules in dorsoventral-mediolateral retinocollicular mapping. Although previous studies have implicated EphB2 forward signalling in mice, the intracellular component of EphB2 essential for retinocollicular mapping is unknown as are the roles for EphB1, ephrin-B1, and ephrin-B2. Here we show that EphB2 tyrosine kinase catalytic activity and EphB1 intracellular si ...[more]

PMID: 21847105

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Project description:Mesenchymal stromal/stem cells (MSC) express the contact-dependent erythropoietin-producing hepatocellular (Eph) receptor tyrosine kinase family and their cognate ephrin ligands, which are known to regulate thymocyte maturation and selection, T-cell transendothelial migration, activation, co-stimulation, and proliferation. However, the contribution of Eph/ephrin molecules in mediating human MSC suppression of activated T-cells remains to be determined. In the present study, we showed that EphB2 and ephrin-B2 are expressed by ex vivo expanded MSC, while the corresponding ligands, ephrin-B1 and EphB4, respectively, are highly expressed by T-cells. Initial studies demonstrated that EphB2-Fc and ephrin-B2-Fc molecules suppressed T-cell proliferation in allogeneic mixed lymphocyte reaction (MLR) assays compared with human IgG-treated controls. While the addition of a third-party MSC population demonstrated dramatic suppression of T-cell proliferation responses in the MLR, blocking the function of EphB2 or EphB4 receptors using inhibitor binding peptides significantly increased T-cell proliferation. Consistent with these observations, shRNA EphB2 or ephrin-B2 knockdown expression in MSC reduced their ability to inhibit T-cell proliferation. Importantly, the expression of immunosuppressive factors, indoleamine 2, 3-dioxygenase, transforming growth factor-?1, and inducible nitric oxide synthase expressed by MSC, was up-regulated after stimulation with EphB4 and ephrin-B1 in the presence of interferon (IFN)-?, compared with untreated controls. Conversely, key factors involved in T-cell activation and proliferation, such as interleukin (IL)-2, IFN-?, tumor necrosis factor-?, and IL-17, were down-regulated by T-cells treated with EphB2 or ephrin-B2 compared with untreated controls. Studies utilizing signaling inhibitors revealed that inhibition of T-cell proliferation is partly mediated through EphB2-induced ephrin-B1 reverse signaling or ephrin-B2-mediated EphB4 forward signaling by activating Src, PI3Kinase, Abl, and JNK kinase pathways, activated by tyrosine phosphorylation. Taken together, these observations suggest that EphB/ephrin-B interactions play an important role in mediating human MSC inhibition of activated T cells.

Dataset Information

Critical roles for EphB and ephrin-B bidirectional signalling in retinocollicular mapping.

Publications

Critical roles for EphB and ephrin-B bidirectional signalling in retinocollicular mapping.

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