Wiring the Binocular Visual Pathways

Abstract

Retinal ganglion cells (RGCs) extend axons out of the retina to transmit visual information to the brain. These connections are established during development through the navigation of RGC axons along a relatively long, stereotypical pathway. RGC axons exit the eye at the optic disc and extend along the optic nerves to the ventral midline of the brain, where the two nerves meet to form the optic chiasm. In animals with binocular vision, the axons face a choice at the optic chiasm-to cross the midline and project to targets on the contralateral side of the brain, or avoid crossing the midline and project to ipsilateral brain targets. Ipsilaterally and contralaterally projecting RGCs originate in disparate regions of the retina that relate to the extent of binocular overlap in the visual field. In humans virtually all RGC axons originating in temporal retina project ipsilaterally, whereas in mice, ipsilaterally projecting RGCs are confined to the peripheral ventrotemporal retina. This review will discuss recent advances in our understanding of the mechanisms regulating specification of ipsilateral versus contralateral RGCs, and the differential guidance of their axons at the optic chiasm. Recent insights into the establishment of congruent topographic maps in both brain hemispheres also will be discussed.

Keywords: axon guidance; neurogenesis; progenitor cell; projection; refinement; retina.

Figure 1

(A) Organization of the retina. All visual information regarding the outside world reaches the brain through the retina, which is composed of 3 layers of cells and two layers made up of connections between these cells. From inside to outside these are: the ganglion cell layer (GCL), containing nuclei of RGCs and displaced amacrine cells; the inner plexiform layer (IPL) where synapses between the bipolar cell axons and the dendrites of the ganglion and amacrine cells take place; the inner nuclear layer (INL), containing the nuclei and cell bodies of the bipolar, horizontal, and amacrine cells as well as Müller glial cells; the outer plexiform layer (OPL) where the projections of rods and cones are located and synapse with dendrites of bipolar and horizontal cells, and the outer nuclear layer (ONL), containing the cell bodies of the rods and cones which are the light detectors. The outer segments of photoreceptor cells associate with the retinal pigmented epithelium (RPE). (B) Transcription factors are expressed in the progenitor cells of the embryonic retina and regulate retinal neurogenesis and cell fate specification. (C) Regulated by Msx1 and CyclinD2, progenitor cells from the ciliary margin zone (CMZ), at the periphery of the retina, can proliferate and differentiate into all seven major retinal cell types, including ipsilaterally and contralaterally projecting RGCs.

Figure 2

Contralaterally projecting RGCs originate throughout the retina, are specified by SoxC genes and express Nrp1, Nr-CAM and Plexin A1. Ipsilaterally projecting RGCs originate in the ventrotemporal retina in mouse, are specified by Zic2 and express EphB1, Boc and Sert. This bestows ipsilaterally and contralaterally projecting axons with differential responsiveness to cues arrayed at the chiasm midline. All RGC axons are repelled by Slits, which constrain the axons to the optic pathway. Ipsilaterally projecting RGCs are repelled away from the midline by ephrinB2, localised to radial glia at the ventral diencepahlic midline, and Shh originating from contralaterally projecting RGC axons. Crossing of contralaterally projecting axons is promoted by VEGF-A and a complex formed from Nr-CAM, Sema6D and PlexinA1. The time course during which ipsilaterally (iRGCs) and contralaterally (cRGCs) projecting RGCs are generated in mice also is shown. D, dorsal, V, ventral.

Figure 3

Establishment of RGC axon organisation in the mouse superior colliculus. (A) RGC axons map topographically in the superficial superior colliculus. (B) Retinotopic map formation is regulated by the interaction of ephrin/Eph gradients. EphAs are expressed in an increasing nasal-temporal gradient in the retina, whereas ephrinA ligands are expressed in an increasing anterior-posterior gradient in the superior colliculus. In the dorsal-ventral axis, a gradient of EphBs is expressed highest in the ventral retina, while a gradient of ephrinBs is highest in the medial superior colliculus. RGC axons initially overshoot their termination zone then retract by the elimination of overextended branches. This refinement process is regulated by activity as well as molecular factors. (C) Based on a mathematical model, a retina–retina (R–R) connection may enable the synchronization of retinal waves from each eye and the establishment of bilaterally congruent maps through symmetrical refinement. In the absence of a retina-retina connection (w/o R–R connection), retinal refinement in each hemisphere may be different generating a non-continuous topographic map.