PLOS Biology · 18 authors, 4 centres
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Using a novel approach to distinguish M- and L-opsin mRNA in human fetal retinas and retinal organoids, the authors found that M-opsin is expressed before L-opsin and that retinoic acid signaling early in development promotes M cone fate while suppressing L cone fate.
The study used human fetal retinal tissue and retinal organoids to investigate mechanisms specifying M (green) and L (red) cone photoreceptor subtypes. The authors developed a method to visualize M-opsin and L-opsin mRNAs, which are highly similar. M-opsin was detected before L-opsin in early fetal development (day 115), and ALDH genes encoding RA-synthesizing enzymes were highly expressed early (around day 55) and decreased over time. RA addition to retinal organoids before day 60 promoted M cone fate and suppressed L cone fate. A noncoding polymorphism in NR2F2, a mediator of RA signaling, was associated with natural variation in M and L cone ratios across a human population sample. Limitations include restricted access to human developmental tissue, inability to experimentally manipulate fetal tissue directly, and the challenge of studying a developmentally inaccessible late fetal time point. Together, the data support a model in which RA signaling is high early to generate M cones and low later to yield L cones.
