Silencing of EphA3 through a cis interaction with ephrinA5

EphAs and ephrinAs are expressed in multiple areas of the developing brain in overlapping countergradients, notably in the retina and tectum. Here they are involved in targeting retinal axons to their correct topographic position in the tectum. We have used truncated versions of EphA3, single-amino acid point mutants of ephrinA5 and fluorescence resonance energy transfer technology to uncover a cis interaction between EphA3 and ephrinA5 that is independent of the established ligand-binding domain of EphA3. This cis interaction abolishes the induction of tyrosine phosphorylation of EphA3 and results in a loss of sensitivity of retinal axons to ephrinAs in trans. Our data suggest that formation of this complex transforms the uniform expression of EphAs in the nasal part of the retina into a gradient of functional EphAs and has a key role in controlling retinotectal mapping.