Abstract
BackgroundIn the auditory brainstem, ventral cochlear nucleus (VCN) axons project to the contralateral, but not ipsilateral, medial nucleus of trapezoid body (MNTB), terminating in the calyx of Held. Dorsal VCN neurons, representing high frequencies, synapse with medial MNTB neurons, while low frequency-coding ventral VCN neurons synapse with lateral MNTB neurons, reflecting tonotopic organization. The mechanisms that ensure strictly contralateral targeting and topographic ordering are incompletely understood. Here we examined the roles of ephrin-A signaling in both types of targeting.ResultsEphrin-A2 and ephrin-A5 are expressed in VCN cells during late embryonic and early postnatal development. At these ages ephrin-A2 is expressed in axons surrounding MNTB and ephrin-A5 is expressed in MNTB principal neurons. Ephrin-A2/A5 double knockout mice displayed axon targeting errors in which VCN axons project to MNTB on both sides of the brainstem, where they terminate in calyceal endings. Ephrin-A2 and ephrin-A5 single knockout mice showed a similar phenotype. In contrast to effects on contralateral targeting, ephrin-A2/A5 double knockout mice showed no defects in formation of tonotopically ordered projections from VCN to MNTB.ConclusionsThese findings demonstrate that distinct mechanisms regulate targeting of VCN axons to the contralateral MNTB and targeting to appropriate tonotopic locations. Ephrin-A signaling plays a similar role to ephrin-B signaling in the VCN-MNTB pathway, where both classes normally prevent formation of calyceal projections to ipsilateral MNTB. These classes may rely in part on common signaling pathways.
Highlights
In the auditory brainstem, ventral cochlear nucleus (VCN) axons project to the contralateral, but not ipsilateral, medial nucleus of trapezoid body (MNTB), terminating in the calyx of Held
Developmental expression patterns Ephrin-A2 expression We examined expression of ephrin-A2 in the auditory brainstem during the development of the VCN-MNTB pathway
At P12 very little expression was seen in MNTB (Fig. 1g) and expression in VCN had diminished in comparison to younger ages (Fig. 1h)
Summary
Ventral cochlear nucleus (VCN) axons project to the contralateral, but not ipsilateral, medial nucleus of trapezoid body (MNTB), terminating in the calyx of Held. Ventral cochlear nucleus (VCN) neurons receive input from central projections of spiral ganglion cells. VCN globular bushy cell axons cross the midline and terminate in the contralateral medial nucleus of the trapezoid body (MNTB) with large specialized endings known as calyces of Held [1]. MNTB neurons send inhibitory projections to ipsilateral LSO, where the balance of excitation and inhibition is used to determine interaural intensity differences. During development VCN axons initially reach the midline by embryonic day 13 (E13) and extend to the contralateral MNTB by E17 [3, 4]. The protracted and orderly growth of these axons reflects the coordinated activity of several families of axon guidance molecules
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