EPHRIN-A1 and -A2 act as positive growth factors for developing spiral ganglion radial bundles

During the formation of the auditory system in mammals, spiral ganglion neurons (SGNs) form ribbon-type synapses with hair cells in the cochlea to establish the first "sensorineural" component of sound transduction. Ahead of synapse formation in the cochlea, the SGNs undergo migration and extension with developing Schwann and otic mesenchyme cells to form radial bundles, fasciculated groups of nerve fibers found between the SGN somata and hair cells. Thus far, reports have shown that Eph/Ephrin signaling is important for the formation of radial bundles. Here, we show that EPHRIN-A1 and -A2 are broadly expressed in the developing cochlea during periods of SGN peripheral axon extension. Confronting spiral ganglion explants with either EPHRIN-A1- or -A2-Fc in vitro promoted neurite extension and reduced fasciculation. EPHRIN-A1- or -A2-Fc treatments also led to increased levels of phosphorylated ERBB2 immunoreactivity in Schwann cells, suggesting a role for developing glia. Loss of Efna1 and Efna2 in mouse models led to approximately a 25 % reduction in SGN peripheral axon extension, an effect that was maintained into adulthood. Overall, the data presented here indicate that EPHRIN-A1 and -A2 are important for normal patterns of cochlear innervation in that they serve as positive growth factors for developing radial bundles, possibly by stimulating Schwann cells.