Temporal regulation of green and red cone specification in human retinas and retinal organoids

Hadyniak, S. E.; Eldred, K. C.; Brenerman, B.; Hussey, K. A.; McCoy, R. C.; Sauria, M. E. G.; Kuchenbecker, J. A.; Neitz, M.; Neitz, J.; Taylor, J.; Johnston, R. J.

doi:10.1101/2021.03.30.437763

bioRxiv · 10.1101/2021.03.30.437763

Temporal regulation of green and red cone specification in human retinas and retinal organoids

Hadyniak, S. E.·Eldred, K. C.·Brenerman, B.·Hussey, K. A.·McCoy, R. C.·Sauria, M. E. G.·Kuchenbecker, J. A.·Neitz, M.·Neitz, J.·Taylor, J.·Johnston, R. J.

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Abstract

Trichromacy is unique to primates among mammals, enabled by blue (short/S), green (medium/M), and red (long/L) cones. In humans 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, but not L-opsin, was observed 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.

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Hadyniak, S. E., Eldred, K. C., Brenerman, B., Hussey, K. A., McCoy, R. C., Sauria, M. E. G., Kuchenbecker, J. A., Neitz, M., Neitz, J., Taylor, J., Johnston, R. J.. 2021-03-31. Temporal regulation of green and red cone specification in human retinas and retinal organoids. https://doi.org/10.1101/2021.03.30.437763

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