The interaction between F3 immunoglobulin domains and protein tyrosine phosphatases ζ/β triggers bidirectional signalling between neurons and glial cells

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Abstract
F3, a mouse glycosyl-phosphatidylinositol anchored molecule of the immunoglobulin superfamily, is known to influence axonal growth and fasciculation via multiple interactions of its modular immunoglobulin-like domains. We prepared an Fc chimeric molecule (F3IgFc) to identify molecules interacting with these domains and characterize the functional impact of the interactions. We affinity-isolated tenascin-C and isoforms of the proteoglycan-type protein tyrosine phosphatases ζ/β (PTPζ/RPTPβ) from extracts of developing mouse brain. We showed that both PTPζ/RPTPβ and tenascin-C can bind directly to F3, possibly in an exclusive manner, with the highest affinity for the F3–PTPζ/RPTPβ interaction. We observed a strong binding of F3IgFc-coated fluorospheres to astrocytes in neural primary cultures and to C6 astrocytoma cells, and demonstrated, in antibody perturbation experiments, that F3-Ig binding on astrocytes depends on its interaction with PTPζ/RPTPβ. We also found by confocal analysis that tenascin-C and PTPζ/RPTPβ were colocalized on astrocytes which suggests a complex interplay of interactions between PTPζ/RPTPβ, tenascin-C and F3. We showed that the interaction between PTPζ/RPTPβ and F3-Ig-like domains can trigger bidirectional signalling. C6 glia-expressed PTPζ/RPTPβ stimulated neurite outgrowth by cortical and cerebellar neurons, whereas preclustered F3IgFc specifically modified the distribution of phosphotyrosine labelling in these glial cells. Both effects could be prevented and/or mimicked by anti-F3 and anti-6B4PG antibodies. These results identify F3 and PTPζ/RPTPβ as potential mediators of a reciprocal exchange of information between glia and neurons.

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