TheAtoh7remote enhancer provides transcriptional robustness during retinal ganglion cell development

Significance Vertebrate retinal ganglion cells (RGCs) transmit all visual signals from the eye to the brain, are the pathogenic target in glaucoma, and require the Atoh7 competence factor to develop from multipotent progenitors. Atoh7 transcription is controlled by dual cis regulatory elements, including a remote shadow enhancer (SE). In humans, loss of the SE causes NCRNA disease, with congenital blindness due to optic nerve aplasia. We generated a mouse Atoh7 SE deletion model and analyzed its effects on transcription, retinal histology, and chromatin architecture. The mutant mice express 80% less Atoh7 mRNA but retain optic nerves, unlike NCRNA patients. By systematically varying dosage in a genotypic series, we show how the dual enhancers maintain robust plasticity during RGC genesis.