Ephrin-A3 Is Required for Tonotopic Map Precision and Auditory Function in the Mouse Auditory Brainstem

Tonotopy is a prominent feature of the vertebrate auditory system and forms the basis for sound discrimination, but the molecular mechanism underlying its formation remain largely elusive. Ephrin/Eph signaling is known to play important roles in axon guidance during topographic mapping in other sensory systems. Here, we determined that ephrin-A3 molecules are expressed in a ventral to dorsal descending gradient along the tonotopic axis in developing mouse cochlear nucleus. During cochlear nucleus innervation by auditory nerve fibers, ephrin-A3 forward signaling can repel these fibers in a stage-dependent manner. In ephrin-A3 mutant animals, the tonotopic map is degraded and isofrequency bands of neuronal activation become imprecise in the anteroventral cochlear nucleus. Ephrin-A3 mutants also exhibit a delayed second wave in auditory brainstem responses and impaired detection sound frequency changes. Our findings establish an essential role for ephrin-A3 in forming precise tonotopy in the auditory brainstem to ensure accurate sound discrimination.