Pro-neurotrophins secreted from retinal ganglion cell axons are necessary for ephrinA-p75(NTR)-mediated axon guidance

BACKGROUND: Retinotectal map formation develops via topographically specific guidance and branching of retinal axons in their target area. This process is controlled, in part, by reverse signalling of ephrinAs expressed on retinal axons. As glycosylphosphatidylinositol-anchored molecules, ephrinAs require transmembrane co-receptors to exert this function, for which the two neurotrophin receptors, p75(NTR )and TrkB, were recently proposed. RESULTS: We show here that the ligands for these receptors, the brain-derived neurotrophic factor precursor (proBDNF) and its processed form, BDNF, respectively, control the branching of retinal axons antagonistically, which they mediate by inducing the corresponding neurotrophin receptor-ephrinA complexes. Moreover, scavenging proneurotrophins, by adding antibodies specific for the pro-domain of proBNDF or a soluble extracellular domain of p75(NTR), abolish repellent ephrinA reverse signalling in the stripe assay. CONCLUSIONS: This indicates that retinal cells secrete proneurotrophins, inducing the ephrinA-p75(NTR )interaction and enabling repellent axon guidance. The antagonistic functions of proBDNF and BDNF raise the possibility that topographic branching is controlled by local control of processing of proneurotrophins.