Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina

Optic nerve formation requires precise retinal ganglion cell (RGC) axon pat hfinding within the retina to the optic disc, the molecular basis of which is not well understood. At CNS targets, interactions between Eph receptor t yrosine kinases on RGC axons and ephrin ligands on target cells have been i mplicated in formation of topographic maps. However, studies in chick and m ouse have shown that both Eph receptors and ephrins are also expressed with in the retina itself, raising the possibility that this receptor-ligand fam ily mediates aspects of retinal development. Here, we more fully document t he presence of specific EphB receptors and B-ephrins in embryonic mouse ret ina and provide evidence that EphB receptors are involved in RGC axon pathf inding to the optic disc, We find that as RGC axons begin this pathfinding process, EphB receptors are uniformly expressed along the dorsal-ventral re tinal axis. This is in contrast to the previously reported high ventral-low dorsal gradient of EphB receptors later in development when RGC axons map to CNS targets. We show that mice lacking both EphB2 and EphB3 receptor tyr osine kinases, but not each alone, exhibit increased frequency of RGC axon guidance errors to the optic disc, In these animals, major aspects of retin al development and cellular organization appear normal, as do the expressio n of other RGC guidance cues netrin, DCC, and L1, Unexpectedly, errors occu r in dorsal but not ventral retina despite early uniform or later high vent ral expression of EphB2 and EphB3, Furthermore, embryos lacking EphB3 and t he kinase domain of EphB2 do not show increased errors, consistent with a g uidance role for the EphB2 extracellular domain. Thus, while Eph kinase fun ction is involved in RGC axon mapping in the brain, RGC axon pathfinding wi thin the retina is partially mediated by EphB receptors acting in a kinase- independent manner.