Human macula formation involves two waves of retinoic acid signaling suppression via CYP26A1 regulating cell cycle exit and cone specification

The human macula is a specialized, M/L cone-rich region of the eye, critical for high acuity vision, but little is known about the pathways regulating its development. Transcriptional regulation by Retinoic Acid (RA) is essential for many aspects of human eye development. Here, we report a striking biphasic expression of the RA-catabolizing enzyme, CYP26A1, in early human macular development between post-conception weeks 6-17. Early inhibition of RA signaling in human retinal organoids (hROs) prompts early cell cycle exit, and an increase in cone photoreceptors, while late inhibition alters cone subtype specification. Conversely, FGF8, which is negatively regulated by RA and vital for High Acuity Area specification in chick, is not expressed in the nascent human macula and had no effect on hRO photoreceptor fate.