Mapping Labels in the Human Developing Visual System and the Evolution of Binocular Vision

Abstract

Topographic representation of visual fields from the retina to the brain is a central feature of vision. The development of retinotopic maps has been studied extensively in model organisms and is thought to be controlled in part by molecular labels, including ephrin/Eph axon guidance molecules, displayed in complementary gradients across the retina and its targeting areas. The visual system in these organisms is primarily monocular, with each retina mapping topographically to its contralateral target. In contrast, mechanisms of retinal mapping in binocular species such as primates, characterized by the congruent, aligned mapping of both retinas onto the same brain target, remain completely unknown. Here, we show that the distribution of ephrin/Eph genes in the human developing visual system is fundamentally different from what is known in model organisms. In the human embryonic retina, EphA receptors are displayed along two gradients, sloping down from the center of the retina to its periphery. The EphB1 receptor, which controls the ipsilateral routing of retinal axons in the mouse, is expressed throughout the human temporal retina in coordination with the changes in EphA gene expression. In the dorsal lateral geniculate nucleus, ephrin-A/EphAs are displayed along complementary retinotopic gradients. Our data point to an evolutionary model in which the coordinated divergence of the distribution of the receptors controlling retinal guidance and retinal mapping enabled the emergence of a fully binocular system. They also indicate that ephrin/Eph signaling plays a potentially major role in the development of neuronal connectivity in humans.

Bilateral visual field maps in a patient with only one hemisphere

“…Crossing in Optic Chiasm. Perhaps the most unexpected response is the rerouting of optic nerve fibers in the chiasm because the decision to cross or to stay on the ipsilateral side is thought to depend on molecular cues (Eph-B1, Eph-A5-6) that are expressed as gradients in the retina, serving as a label for the origin of retinal axons and then interact with guiding receptor cues (Ephrin-B2) at the optic chiasm, allowing the crossing of fibers from the nasal and preventing such crossing of fibers from the temporal retinae (6,9,32). In human embryos the optic discs start to develop at Carnegie stage 9 (day 25), the diencephalon becomes distinguishable at Carnegie stage 10 (day 28), and ganglion cell axons reach the optic chiasm at Carnegie stage 20 (approximately 49 days of gestation; (33); for more information see SI Text).…”

“…The retinotopic maps and their interocular alignment also depend on gradient matching between markers of retinal and thalamic origin (Ephrin-A and -B) (9,32,35). Ephrin-A5 determines an anterior to posterior (and dorsal to ventral) gradient in the LGN onto which ganglion cell axons align from the periphery to the center.…”

“…Ephrin-A5 determines an anterior to posterior (and dorsal to ventral) gradient in the LGN onto which ganglion cell axons align from the periphery to the center. The density of Eph-A5-6 receptor is highest in the center of the human retina and levels off toward the nasal as well as the temporal fringe of the retina (32). The Eph-A5-6 gradients are therefore ideally suited to guide the projections from both eyes to retinotopically corresponding laminae in the LGN.…”

Dynamics of Spontaneous Activity in the Fetal Macaque Retina during Development of Retinogeniculate Pathways

“…pression of axon guidance cues such as ephrin-As can induce retinotopy and eyespecific circuitry in the dlgn (Huberman et al, 2005b;Lambot et al, 2005;Pfeiffenberger et al, 2005). It remains for future studies to determine the role of axon guidance cues in the development of primate retinogeniculate pathways.…”

Self‐organization in the developing nervous system: Theoretical models

“…As Sperry suggested, in binocular species the nasotemporal retinal axis should not express a uniform but a central-to-peripheral gradient, such that the temporal projection of one eye and the nasal projection of the other eye will map to the same target position (Sperry, 1963). Lambot et al (2005) reported such expression patterns of ephrins and Ephs in developing human retina, confirming Sperry's proposal. This finding emphasizes that, although the mouse is a good model system, it is clearly not sufficient for explaining human development.…”