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J. M. Provis, P. Kozulin, R. Natoli, K. Bumsted O'Brien, M. C. Madigan; A Role for Repellent Ephrin Signalling in Development of the Foveal Avascular Area. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4014.
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© ARVO (1962-2015); The Authors (2016-present)
In the primate macula the density of all neural elements is elevated, and there is a prevalence of ‘midget’ circuits which provide the brain with the detailed spatial and color information characteristic of macular visual function. The peak density of cones occurs in the center of the macula at the fovea, within the foveal avascular area (FAA). In this study we investigated the hypothesis that Eph receptors and ephrins have a role in defining the FAA.
We extracted RNA from human fetal retinas and probed for EphA5-7, EphB2, ephrin B1 and ephrin A1-A5 expression by RT-PCR, then prepared riboprobes for EphA5-7. Paraffin sections of fetal macaque retinas were used to localize Eph expression by in situ hybridization, and immunohistochemistry was used to identify cells immunoreactive for some ephrins. We used confocal microscopy and optical densitometry to analyze the findings.
We identified gradients of EphA6 mRNA expression in the ganglion cell layer (GCL) of fetal macaque retinas, that varied with age. At fetal day (Fd55) EphA6 expression was high at the optic disc and low in the developing macula. At Fd70 and 80, when astrocyte and endothelial cell precursors enter the retina, the gradient was reversed, so that EphA6 expression was lower at the disc. In central retina we also detected a gradient running perpendicular to the retinal surface, such that EphA6 was high in the inner GCL and low in the outer GCL. By Fd110, when the fovea begins to form, the highest levels of EphA6 expression were detected at the macula and developing fovea, and progressively lower levels of expression were detected at increasing distance from the fovea. This pattern of expression persisted into the postnatal period. In double-labeling experiments we found the two ligands for EphA6, ephrin A1 and A4, expressed by Pax2-immunoreactive astrocytes, in the optic nerve head and in the retina.
Peak levels of EphA6 expression at the developing fovea are consistent with EphA6-ephrin A1/A4 repellent signaling that defines a foveal 'no-go' zone for astrocytes, which halts endothelial cell migration and defines the FAA. Prolonged expression of EphA6 at the fovea and in the adjacent retina may explain the known egress of astrocytes from the macula during the late stages of fetal retinal development.
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