Retinoic acid signaling regulates spatiotemporal specification of human green and red cones

PLoS Biol. 2024 Jan 11;22(1):e3002464. doi: 10.1371/journal.pbio.3002464. eCollection 2024 Jan.


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.

MeSH terms

  • Adult
  • Animals
  • Female
  • Humans
  • Mammals / metabolism
  • Opsins / metabolism
  • Placenta* / metabolism
  • Pregnancy
  • Primates
  • Retina / metabolism
  • Retinal Cone Photoreceptor Cells / metabolism
  • Rod Opsins / genetics
  • Tretinoin* / metabolism


  • Tretinoin
  • Opsins
  • Rod Opsins