A Retino-retinal Projection Guided by Unc5c Emerged in Species with Retinal Waves

The existence of axons extending from one retina to the other has been reported during perinatal development in different vertebrates. However, it has been thought that these axons are either a labeling artifact or misprojections. Here, we show unequivocally that a small subset of retinal ganglion cells (RGCs) project to the opposite retina and that the guidance receptor Unc5c, expressed in the retinal region where the retinal-retinal (R-R) RGCs are located, is necessary and sufficient to guide axons to the opposite retina. In addition, Netrin1, an Unc5c ligand, is expressed in the ventral diencephalon in a pattern that is consistent with impeding the growth of Unc5c-positive retinal axons into the brain. We also have generated a mathematical model to explore the formation of retinotopic maps in the presence and absence of a functional connection between both eyes. This model predicts that an R-R connection is required for the bilateral coordination of axonal refinement in species where refinement depends upon spontaneous retinal waves. Consistent with this idea, the retinal expression of Unc5c correlates with the existence and size of an R-R projection in different species and with the extent of axonal refinement in visual targets. These findings demonstrate that active guidance drives the formation of the R-R projection and suggest an important role for these projections in visual mapping to ensure congruent bilateral refinement.