02348nas a2200409   4500000000100000000000100001008003900002260001700041653001100058653002800069653002600097653001400123653001900137653002200156653001100178653001700189100002200206700002300228700002000251700002000271700002400291700001900315700002500334700002600359700001500385700001400400700001800414700001400432700001700446700002600463245009600489856008200585300001300667490000700680520123700687022001401924       0                             d  cJan 11, 202410aAdults10aBright field microscopy10aIn Situ Hybridization10aorganoids10aPhotoreceptors10aRNA hybridization10aRetina10aTransfection1 aSarah E. Hadyniak1 aJoanna F. D. Hagen1 aKiara C. Eldred1 aBoris Brenerman1 aKatarzyna A. Hussey1 aRajiv C. McCoy1 aMichael E. G. Sauria1 aJames A. Kuchenbecker1 aThomas Reh1 aIan Glass1 aMaureen Neitz1 aJay Neitz1 aJames Taylor1 aRobert J. Johnston Jr00aRetinoic acid signaling regulates spatiotemporal specification of human green and red cones  uhttps://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002464  ae30024640 v223 aTrichromacy is unique to primates among placental mammals, enabled by blue (short/S), green (medium/M), and red (long/L) cones. In humans, great apes, and Old World monkeys, cones make a poorly understood choice between M and L cone subtype fates. To determine mechanisms specifying M and L cones, we developed an approach to visualize expression of the highly similar M- and L-opsin mRNAs. M-opsin was observed before L-opsin expression during early human eye development, suggesting that M cones are generated before L cones. In adult human tissue, the early-developing central retina contained a mix of M and L cones compared to the late-developing peripheral region, which contained a high proportion of L cones. Retinoic acid (RA)-synthesizing enzymes are highly expressed early in retinal development. High RA signaling early was sufficient to promote M cone fate and suppress L cone fate in retinal organoids. Across a human population sample, natural variation in the ratios of M and L cone subtypes was associated with a noncoding polymorphism in the NR2F2 gene, a mediator of RA signaling. Our data suggest that RA promotes M cone fate early in development to generate the pattern of M and L cones across the human retina.  a1545-7885