Summary: Researchers have identified a surprising cellular mechanism that allows humans to develop the sharp vision necessary for daytime perception. By using lab-grown retinal organoids, the study found that the foveola—the center of the retina—achieves its high-acuity patterning not through cell migration, as previously believed, but through cell conversion.
A derivative of vitamin A known as retinoic acid initially limits the creation of blue cones, followed by thyroid hormones that trigger remaining blue cones to transform into red and green cones. This discovery upends decades of conventional wisdom and provides a new blueprint for developing cell-based therapies to treat age-related vision disorders.
Key Facts
- Cellular Transformation: The study reveals that blue cones in the central retina actually convert into red and green cones during early fetal development (around week 14).
- Hormonal Orchestration: Two distinct processes drive this patterning: retinoic acid breaks down to limit blue cone production, while thyroid hormones encourage the transition of existing cells.
- Foveola Importance: While the foveola is only a tiny fraction of the retina, it contains the dense red and green cone population responsible for 50% of human visual perception.
Source: Johns Hopkins University
Humans develop sharp vision during early fetal development thanks to an interplay between a vitamin A derivative and thyroid hormones in the retina, Johns Hopkins University scientists have found.
The findings could upend decades of conventional understanding of how the eye grows light-sensing cells and could inform new research into treatments for macular degeneration, glaucoma, and other age-related vision disorders.
Details of the study, which used lab-grown retinal tissue, are published today in Proceedings of the National Academy of Sciences.
“This is a key step toward understanding the inner workings of the center of the retina, a critical part of the eye and the first to fail in people with macular degeneration,” said Robert J. Johnston Jr., an associate professor of biology at Johns Hopkins who led the research.
“By better understanding this region and developing organoids that mimic its function, we hope to one day grow and transplant these tissues to restore vision.”
In recent years, the team pioneered a new method to study eye development using organoids, small tissue clusters grown from fetal cells.
By monitoring these lab-grown retinas over several months, the researchers discovered the cellular mechanisms that shape the foveola—a central retinal region responsible for sharp vision.
Their research focused on light-sensitive cells that enable daytime vision. These cells develop into blue, green, or red cone cells that have sensitivity to different types of light.
Although the foveola comprises only a small fraction of the retina, it accounts for about 50% of human visual perception. The foveola contains red and green cones but not blue cones, which are distributed more broadly across the rest of the retina.
Humans are unique in having these three types of cones for color vision, allowing people to see a wide spectrum of colors that are relatively rare in other animals. How eyes grow with this distribution of cells has puzzled scientists for decades. Mice, fish, and other organisms commonly used for biological research do not have this patterning of cells, which makes the photoreceptor cells difficult to study, Johnston said.
The Johns Hopkins team concluded the distribution of cones in the foveola results from a coordinated process of cell fate specification and conversion during early development. Initially, a sparse number of blue cones are present in the foveola at weeks 10 through 12. But, by week 14, they transform into red and green cones. The patterning occurs by way of two processes, the new study shows.
First, a molecule derived from vitamin A called retinoic acid is broken down to limit the creation of blue cones. Second, thyroid hormones encourage blue cones to convert into red and green cones.
“First, retinoic acid helps set the pattern. Then, thyroid hormone plays a role in converting the leftover cells,” Johnston said.
“That’s very important because if you have those blue cones in there, you don’t see as well.”
The findings offer a different perspective to the prevailing theory that blue cones migrate to other parts of the retina during development. Instead, the data suggest that these cells convert to achieve optimal cone distribution in the foveola.
“The main model in the field from about 30 years ago was that somehow the few blue cones you get in that region just move out of the way, that these cells decide what they’re going to be, and they remain this type of cell forever,” Johnston said.
“We can’t really rule that out yet, but our data supports a different model. These cells actually convert over time, which is really surprising.”
The insights could pave the way for new therapies for vision loss. Johnston and his team are working to refine their organoid models to better replicate human retina function. These advancements could lead to improved photoreceptors and potential cell-based treatments for eye diseases such as macular degeneration, which have no cure, said author Katarzyna Hussey, a former doctoral student who graduated from Johnston’s lab.
“The goal with using this organoid tech is to eventually make an almost made-to-order population of photoreceptors. A big avenue of potential is cell replacement therapy to introduce healthy cells that can reintegrate into the eye and potentially restore that lost vision,” said Hussey, who is now a molecular and cell biologist at cell therapy company CiRC Biosciences in Chicago.
“These are very long-term experiments, and of course we’d need to do optimizations for safety and efficacy studies prior to moving into the clinic. But it’s a viable journey.”
Key Questions Answered:
A: During early fetal development, yes. The study shows these specific molecules are the “engineers” that set the pattern for sharp sight. While this research focuses on development, maintaining these pathways is crucial for overall eye health.
A: For 30 years, scientists thought these cells were fixed in their identity and simply migrated. Knowing they can change types opens the door to “reprogramming” cells in a lab to create made-to-order tissues for transplants.
A: Macular degeneration targets the center of the retina. By understanding the exact chemical “recipe” used to grow this region, scientists hope to grow healthy retinal tissue in a lab and transplant it to restore lost sight.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this visual neuroscience research news
Author: Hannah Robbins
Source: Johns Hopkins University
Contact: Hannah Robbins – Johns Hopkins University
Image: The image is 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, Kiara C. Eldred, Brian Guy, Clayton P. Santiago, Jingliang Simon Zhang, Ian Glass, Thomas A. Reh, Seth Blackshaw, Loyal A. Goff, and Robert J. Johnston Jr. PNAS
DOI:10.1073/pnas.2510799123
Abstract
A cell fate specification and transition mechanism for human foveolar cone subtype patterning
In the central region of the human retina, the high-acuity foveola is notable for its dense packing of green (M) and red (L) cones and absence of blue (S) cones.
To identify mechanisms that pattern cones in the foveola, we examined human fetal retinas and differentiated retinal organoids. During development, sparse S-opsin-expressing cones are initially observed in the foveola.
Later in fetal development, the foveola contains a mix of cones that either coexpress S- and M/L-opsins or exclusively express M/L-opsin. In adults, only M/L cones are present.
Two signaling pathway regulators are highly and continuously expressed in the central retina: Cytochrome P450 26 subfamily A member 1 (CYP26A1), which degrades retinoic acid (RA) and Deiodinase 2 (DIO2), which promotes thyroid hormone (TH) signaling. Both CYP26A1 mutant organoids and high RA conditions increased the number of S cones and reduced the number of M/L cones in retinal organoids.
In contrast, sustained TH signaling promoted the generation of M/L-opsin-expressing cones and induced M/L-opsin expression in S-opsin-expressing cones, showing that cone fate is plastic.
Our data suggest that CYP26A1 degrades RA to specify M/L cones and limit S cones and that continuous DIO2 expression sustains high levels of TH to transition S-opsin-expressing cones into M/L cone fate, resulting in the foveola containing only M/L cones.
Given the vulnerability of the foveola in macular degeneration and other retinal disorders, these findings provide a mechanistic framework for engineering organoids for therapeutic applications.
