Retinoic acid regulates foveal development in the human retina

The fovea is a region of the human retina specialized for high-acuity vision, with a high density of cones and no rod photoreceptors. Recent studies using retinal organoids indicate that retinoic acid (RA) may play a key role in foveal development: low RA levels in the fovea, maintained by CYP26A1, lead to early cell cycle exit for progenitors and a low rod-to-cone ratio. To test this model in fetal human development, we studied human fetal retina in 3D cultures in the presence of RA and RA inhibitors. We find that inhibition of RA reduces retinal progenitor proliferation and rod development, while a high concentration of RA promotes rod fate and represses cone opsin expression. Moreover, inhibition of RA signaling promotes expression of M/L-opsins over S-opsin, a feature of the fovea. Our results demonstrate that RA levels control several key features of foveal development in human fetal retina.