Data that underlies S7A and S7B Fig.

Trichromacy 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.

三色视觉在胎盘哺乳动物类群中为灵长类所独有，其生理基础依赖于蓝敏（短波长/S）、绿敏（中波长/M）与红敏（长波长/L）视锥细胞（cone）。在人类、类人猿与旧世界猴中，视锥细胞会在M与L型视锥细胞的命运分化方向间做出一种目前尚未明确的选择。为阐明调控M与L型视锥细胞分化的分子机制，我们开发了一种可可视化高度同源的M、L视蛋白mRNA表达情况的实验方法。在人类胚胎眼部发育早期，我们观测到M视蛋白的表达早于L视蛋白，这提示M型视锥细胞的生成时间早于L型视锥细胞。在成人人体视网膜组织中，发育时序较早的中央视网膜区域同时存在M与L型视锥细胞；而发育时序较晚的周边视网膜区域则以高比例的L型视锥细胞为主。视黄酸（RA）合成酶在视网膜发育早期呈高表达状态。早期高水平的视黄酸信号足以在视网膜类器官中促进M型视锥细胞的命运分化，并抑制L型视锥细胞的命运分化。通过对人类人群样本的分析，我们发现M与L型视锥细胞亚型比例的自然变异与NR2F2基因的一处非编码多态性存在关联——该基因是视黄酸信号通路的介导因子。我们的研究数据表明，视黄酸可在发育早期促进M型视锥细胞的命运分化，从而在人类视网膜中形成M与L型视锥细胞的分布格局。