EPHRIN-A5 (AL-1 RAGS) IS ESSENTIAL FOR PROPER RETINAL AXON GUIDANCE AND TOPOGRAPHIC MAPPING IN THE MAMMALIAN VISUAL-SYSTEM/

Ephrin-A5 (AL-1/RAGS), a ligand for Eph receptor tyrosine kinases, rep els retinal axons in vitro and has a graded expression in the superior colliculus (SC), the major midbrain target of retinal ganglion cells. These properties implicate ephrin-A5 in the formation of topographic maps, a fundamental organizational feature of the nervous system. To t est this hypothesis, we generated mice lacking ephrin-A5. The majority of ephrin-A5(-/-) mice develop to adulthood, are morphologically inta ct, and have normal anterior-posterior patterning of the midbrain. How ever, within the SC, retinal axons establish and maintain dense arbori zations at topographically incorrect sites that correlate with locatio ns of low expression of the related ligand ephrin-A2. In addition, ret inal axons transiently over-shoot the SC and extend aberrantly into th e inferior colliculus (IC). This defect is consistent with the high le ver of ephrin-A5 expression in the IC and the finding that retinal axo n growth on membranes from wild-type IC is inhibited relative to that on membranes from ephrin-A5(-/-) IC. These findings show that ephrin-A 5 is required for the proper guidance and mapping of retinal axons in the mammalian midbrain.