Abstract
Optic neuropathy (ON) is a leading cause of irreversible blindness, but the precise factors contributing to neuronal damage remain unclear. Research has identified 'ephrin signaling' as a key dysregulated pathway in the early stages of ON with varying causes. During development, ephrin signaling orchestrates retinotopic mapping by influencing neuronal membrane cytoskeletal dynamics through repulsive mechanisms. However, little is known about the role of ephrin signaling in the post-natal visual system and its relationship with ON onset. To investigate this, we conducted a study using postnatal mouse retinas. Mass spectrometry analysis revealed the presence of seven Eph receptors. We induced ON through optic nerve crush (ONC) and analyzed proteomic changes during the acute phase of neuropathic onset. Confocal and super-resolution microscopy showed the cellular localization of activated Eph receptors post-ONC injury, and we assessed the neuroprotective effects of Eph receptor inhibitors. Our findings indicate that diverse Eph receptors are functionally present in the postnatal mammalian retina, capable of influencing various biological processes. Pan-Eph receptor activation contributes to ON onset, with a preference for neuronal processes in the inner retina following optic nerve injury. Importantly, Eph receptor activation occurs before neuronal loss, and inhibiting Eph receptors shows a neuroprotective effect on retinal ganglion cells (RGCs). This study underscores the significance of investigating the repulsive ephrin pathway in early optic neuropathies and offers a comprehensive characterization of the receptors present in the developed mouse retina, which is relevant to both normal functioning and disease processes.