Ephrin-A2 and ephrin-A5 guide contralateral targeting but not topographic mapping of ventral cochlear nucleus axons

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.

EphA2 and Ephrin-A5 Guide Eye Lens Suture Alignment and Influence Whole Lens Resilience

“…In the retina, brain, and other somatosensory systems, attraction and repulsion mediated by gradients of Ephs and ephrins, including ephrin-A5, are responsible for normal pattering of axons to determine unique synaptic targets. 41 – 44 Signaling through EphA2 and ephrin-A5 could provide cues for elongating fiber cell tips to detach from the apical surface of anterior epithelial cells or the posterior lens capsule to contact neighboring fibers to form the lens suture. It is not clear at this time whether this signaling is through interactions between EphA2 and ephrin-A5 or if there are other ephrin ligands or Eph receptors required for formation of the normal lens suture.…”

Axonal Projection Patterns of the Dorsal Interneuron Populations in the Embryonic Hindbrain

“…A series of elegant studies in the auditory hindbrain uncovered the role of EphA4/B2/B3 receptors in regulating axonal connectivity of the dA1-derived NM-NL binaural circuit in avian, or in the projection of the VCN nuclei, which consist of dA1 and dB1 neurons, to the contralateral MNTB in mice. Disruption in these receptors in chick or mouse embryos resulted in axonal misrouting and various targeting errors (Cramer et al, 2004(Cramer et al, , 2006Huffman and Cramer, 2007;Hsieh et al, 2010;Abdul-latif et al, 2015). EphA-ephrinA interactions also play a role in guiding the turning point of axons that project from caudal vestibular neurons (cC-VC) once they cross the midline and extend longitudinally toward the cerebellum (Zhu et al, 2006).…”

Eph-ephrin signaling in nervous system development

“…However, Eph-ephrin signaling also contributes significantly to selection of discrete, or discontinuous, synaptic targets, and these modes of targeting often occur together in a single neural pathway. Interestingly, the function of individual Eph or ephrin family members is specialized within a structure, so that family members regulating topography are distinct from those regulating modular 48 , laminar 49 , or ipsilateral versus contralateral 50 axon targeting decisions.…”

“…This role has been demonstrated in the auditory brainstem pathway from the cochlear nucleus to the medial nucleus of the trapezoid body, a strictly contralateral projection in the normal brain. Mutations that reduce reverse signaling through ephrin-B proteins 59 and null mutations in ephrin-A2 or ephrin-A5 (or both) similarly reduce the specificity of this pathway, resulting in a significant ipsilateral projection 50 . The similarity in these phenotypes suggests crosstalk between the classes and redundancy in cues for generating the crossed projection.…”