Summary: Researchers have discovered an unexpected cellular mechanism that shapes our sharp, daytime vision. Using lab-grown retinal organoids, the team found that the human foveola—the tiny central zone of the retina responsible for high-acuity sight—achieves its specialized arrangement of photoreceptors not by cells migrating outward, as long believed, but by a conversion of cell identity.
A metabolite of vitamin A, retinoic acid, initially acts to limit the production of blue-sensitive cone cells. Later, thyroid hormone signaling prompts the remaining blue cones to convert into red and green cones. This two-step hormonal orchestration overturns decades of assumptions about how the central retina develops and supplies a new framework for creating cell-based therapies to treat macular degeneration and other age-related visual disorders.
Key Facts
- Cell identity conversion: Blue (S) cones that appear early in fetal development in the foveola are converted into red (L) and green (M) cones by mid-fetal stages, rather than migrating away.
- Hormonal control: Retinoic acid breakdown limits S-cone formation, while sustained thyroid hormone signaling drives the transition from S- to M/L-cone identity.
- Foveola significance: Although very small, the foveola contains densely packed L and M cones and supports roughly half of human visual perception, making its correct patterning essential for sharp central vision.
Source: Johns Hopkins University
Sharp, daylit vision emerges during early fetal development through a controlled interplay between a vitamin A derivative and thyroid hormones within the retina, according to researchers at Johns Hopkins University.
These findings, based on experiments with human fetal tissue and retinal organoids grown in the lab, challenge long-standing views on photoreceptor development. The study appears in Proceedings of the National Academy of Sciences and lays out a molecular explanation for how the foveola becomes specialized to support high-acuity color vision.
“Understanding the inner workings of the retina’s center is critical because this region is the first to deteriorate in macular degeneration,” said Robert J. Johnston Jr., associate professor of biology at Johns Hopkins, who led the research. “By building organoids that faithfully reproduce these processes, we aim to one day grow replacement tissue that could restore vision.”
Johnston’s team has refined methods for producing retinal organoids—three-dimensional cellular structures derived from fetal cells that recapitulate many aspects of human retinal development. Tracking these organoids over several months allowed the scientists to observe when and how cone subtypes emerge and change in the developing foveola.
Cones are photoreceptors tuned to different wavelengths of light: S-cones (blue), M-cones (green), and L-cones (red). Humans are among the few species with this trichromatic system, which supports a broad and nuanced color vision. The foveola is densely packed with L and M cones but lacks S cones; understanding how this pattern arises has been challenging because common model organisms do not reproduce the same cellular distribution.
The new evidence indicates a coordinated two-step mechanism. Early in development, small numbers of S-cones appear in the foveola between roughly 10 and 12 weeks. By around week 14, many of those S-cones begin expressing M/L opsins and adopt M or L cone properties. The shift occurs through the combined action of two biochemical pathways: CYP26A1-mediated degradation of retinoic acid reduces ongoing S-cone specification, while the enzyme DIO2 sustains thyroid hormone signaling that actively induces S-to-M/L cone transitions.
Experiments in organoids support this model. Conditions that increase retinoic acid or disrupt CYP26A1 raise the number of S-cones and reduce M/L cones. Conversely, prolonged thyroid hormone signaling promotes M/L identity and can induce M/L opsin expression in cells that initially expressed S-opsin, demonstrating that cone fate remains plastic during a critical developmental window.
“Retinoic acid helps set the initial pattern, and thyroid hormone converts the remaining cells,” Johnston explained. “If blue cones remained in the foveola, visual acuity would be compromised—this conversion is essential to produce the dense L/M cone mosaic that underlies sharp central vision.”
This conversion model contrasts with the older view—that a small population of S-cones simply migrates out of the foveolar region. While migration cannot be entirely ruled out, the organoid and fetal tissue data strongly support a fate-change mechanism. That discovery has practical implications: if cone identity can be re-specified, researchers can explore reprogramming strategies to produce customized photoreceptors for transplantation.
The team is improving organoid techniques to more closely mimic human retinal architecture and function. Katarzyna Hussey, a former doctoral student in Johnston’s lab and co-author of the study, emphasized the therapeutic potential: “The aim is to generate near–made-to-order populations of photoreceptors for cell-replacement therapies. These are long-term efforts that require extensive optimization for safety and efficacy, but the mechanistic blueprint we’ve uncovered makes that goal more tangible.”
Key Questions Answered:
A: During early fetal development, yes. The study identifies retinoic acid and thyroid hormone as critical signals that pattern the foveola. While the research centers on development, these pathways are important for general retinal health.
A: If cone identity is changeable, scientists can consider reprogramming strategies to create desired photoreceptor types in vitro. That opens possibilities for tailored cell therapies and improves our understanding of retinal plasticity.
A: Macular degeneration damages the central retina. By defining the chemical “recipe” that produces a healthy foveola, researchers can work toward growing and transplanting replacement retinal tissue to recover central vision.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by editorial staff.
- Additional context was added by the reporting team to clarify implications for therapy and research.
About this visual neuroscience research news
Author: Hannah Robbins
Source: Johns Hopkins University
Contact: Hannah Robbins – Johns Hopkins University
Image: Image credited to Neuroscience News
Original Research: Open access. “A cell fate specification and transition mechanism for human foveolar cone subtype patterning” by Katarzyna A. Hussey et al., published in Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2510799123
Abstract
A cell fate specification and transition mechanism for human foveolar cone subtype patterning
The human foveola, the central high-acuity region of the retina, is densely packed with green (M) and red (L) cones and is notable for an absence of blue (S) cones. To uncover how this pattern emerges, the researchers examined human fetal retinas and differentiated retinal organoids. Sparse S-opsin–expressing cones appear early in the foveola, but later stages show cones that coexpress S- and M/L-opsins or exclusively express M/L-opsins. In adults, only M/L cones remain.
Two signaling regulators are highly expressed in the central retina: CYP26A1, which degrades retinoic acid and limits S-cone specification, and DIO2, which enhances thyroid hormone signaling and promotes M/L-cone identity. Manipulating these pathways in organoids demonstrated that increased retinoic acid or loss of CYP26A1 increases S cones, whereas sustained thyroid hormone signaling favors M/L cones and can convert S-opsin–expressing cones into M/L-opsin–expressing cones. These results indicate that retinoic acid degradation specifies M/L cones and limits S cones, while continuous thyroid hormone signaling transitions residual S cones into M/L cone fate, shaping the adult foveolar mosaic. Given the foveola’s vulnerability in macular degeneration and other retinal disorders, these findings provide a mechanistic framework for engineering retinal organoids for therapeutic applications.