Magnitude of binocular vision controlled by islet-2 repression of a genetic program that specifies laterality of retinal axon pathfinding

Pathfinding of retinal ganglion cell (RGC) axons at the midline optic chiasm determines whether RGCs project to ipsilateral or contralateral brain visual centers, critical for binocular vision. Using IsI2(tau-lac)Z knockin mice, we show that the LIM-homeodomain transcription factor IsI2 marks only contralaterally projecting RGCs. The transcription factor Zic2 and guidance receptor EphB1, required by RGCs to project ipsilaterally, colocalize in RGCs distinct from IsI2 RGCs in the ventral-temporal crescent (VTC), the source of ipsilateral projections. IsI2 knockout mice have an increased ipsilateral projection originating from significantly more RGCs limited to the VTC. IsI2 knockouts also have increased Zic2 and EphB1 expression and significantly more Zic2 RGCs in the VTC. We conclude that IsI2 specifies RGC laterality by repressing an ipsilateral pathfinding program unique to VTC RGCs and involving Zic2 and EphB1. This genetic hierarchy controls binocular vision by regulating the magnitude and source of ipsilateral projections and reveals unique retinal domains.