Isl1 Controls Axon Pathfinding of Retinal Ganglion Cells in the Binocular Visual Pathway

Axons of retinal ganglion cells (RGCs) face a choice to project ipsilaterally or contralaterally at the optic chiasm. This decision is crucial for the establishment of binocular vision in mammals. The transcription factor ZIC2 is well known as a key determinant of ipsilateral RGC identity, however the transcriptional programs controlling contralateral RGC identity have only begun to be elucidated more recently. Here we show that inactivation of the LIM-HD transcription factor ISL1 results in an expansion of the ZIC2 ⁺ ventrotemporal (VT) domain of the retina and an increase in ipsilateral projections from outside the VT retina. RNA-Seq, gene expression and CUT&Tag analyses show that ISL1 regulates RGC laterality through a set of unique downstream effectors as well as a few common ones, as other transcription factors. Our data also show that RGC axons misrouted at the midline in Isl1 -null mutants could innervate the appropriate eye-specific regions of the dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC), in agreement with earlier studies that have shown that eye specific targeting of visual nuclei in the brain is independent of laterality decisions at the optic chiasm.