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Less clear is what controls the formation of that high-acuity spot at the back of an eye, known in humans as the fovea (Latin for "pit"). Harvard Medical School research now provides insight into this puzzling question through study of an unusual model animal: the chicken.
Connie Cepko PhD, professor of Genetics and Neuroscience at Harvard Medical School (HMS), and Susana da Silva, a postdoctoral candidate in the Cepko lab, find that formation of this high-acuity area in the eye of chicks requires the suppression of retinoic acid. A derivative of vitamin A, retinoic acid is known to play many important roles in embryo development.
In addition to deepening our understanding of how we have sensitive daytime vision, these findings in the chick could help regenerative medicine research model development of the human eye. Research results are reported in the June 22 issue of Developmental Cell. These discoveries in chicks, it they hold true in humans too, might one day help us combat macular degeneration, the leading cause of vision loss in people age 50 and over. The macula is that part of the retina where the fovea is located.
"I think it's important to understand how you build this specialized area in the retina that's responsible for any major activity you do during the day, such as reading, driving, recognizing faces and using the phone," explains da Silva. "It would also be exciting if people can use what we learn from this basic developmental question to treat diseases affecting the retina."
Most of the human retina is lined with rod cells, which allow us to see in dim light. But the fovea is almost entirely cone cells, and responds to color and bright light.
Twenty years ago, a researcher in Cepko's lab discovered that chickens also have a rod-free zone in their retina. Although it's not yet clear how closely chickens' high-acuity areas match ours, Cepko believes it's a good place to start asking questions. Esecially as scientists' usual collection of mammalian model animals — mice, rats, rabbits, guinea pigs, etc. — don't have anything like a fovea. Cepko and da Silva now find there is a complex pattern of cells in the rod-free zone of a chick embryo retina, which form only after a drop in retinoic acid — and that retinoic acid level only drops for a brief moment in the fovea area.
What spurred that drop in retinoic acid? Researchers found the answer is in a shifting balance between enzymes which create and enzymes which destroy retinoic acid.
Enzymes known as retinaldehyde dehydrogenases, or Raldhs, ordinarily produce retinoic acid in the retina. But Cepko and da Silva discovered that as cones and ganglion cells form, levels of two enzymes — Cyp26a1 and Cyp26c1 — surge into the area to break down retinoic acid faster than it can be produced. When retinoic acid levels fall, a protein called fibroblast growth factor 8, or Fgf8, takes off. Fgf8 is a molecule in embryo development that often works with retinoic acid to stimulate cell growth.
Once enzymes Cyp26a1 and Cyp26c1 work is done, they ebb away. This allows Raldhs to rebuild and replenish retinoic acid to the rod-free zone. Cepko and da Silva saw similar expression patterns for Raldhs and Cyp26a1 in human retinal tissue, suggesting that something similar happens within people.
"This is the first mechanism we've uncovered for how this area forms," says Cepko. "We don't know where it will lead, but it's pretty exciting. Stem cell researchers had made remarkable progress in building so-called organoids that mimic human eyes in order to study human health and disease. But they ran into a problem, which our new study may help them resolve.
"People can grow these incredible little eyes from stem cells in petri dishes. But so far, no one's been able to form a fovea," explains Cepko, who is also an HMS professor of ophthalmology at Massachusetts Eye and Ear. She believes the trouble may arise because researchers add retinoic acid to their cell cultures. "We're suggesting that removing retinoic acid at the right time, adding Fgf8 or otherwise manipulating these two molecules may allow them to generate a fovea," she said.
It's also possible that the research will provide a foundation for investigating why the macula is so prone to disease, which could in turn lead to new treatments.
Cepko and da Silva are next planning to study lizards and birds that have two foveae in each eye. Explains Cepko: "Now that we have molecules we can examine, we can ask questions like, 'Does every species with a high-acuity area use the same mechanisms?' If so, we may have inherited it from a common ancestor.
• Retinoic acid (RA) and Fgf8 show tightly circumscribed patterns in the chick retina
• RA negatively regulates Fgf8 expression to form a central high-acuity area
• RA and Fgf8 regulate the distinctive cellular patterns in a high-acuity area
• RA enzymes are also distinctly patterned in human embryonic retinal tissue
Species that are highly reliant on their visual system have a specialized retinal area subserving high-acuity vision, e.g., the fovea in humans. Although of critical importance for our daily activities, little is known about the mechanisms driving the development of retinal high-acuity areas (HAAs). Using the chick as a model, we found a precise and dynamic expression pattern of fibroblast growth factor 8 (Fgf8) in the HAA anlage, which was regulated by enzymes that degrade retinoic acid (RA). Transient manipulation of RA signaling, or reduction of Fgf8 expression, disrupted several features of HAA patterning, including photoreceptor distribution, ganglion cell density, and organization of interneurons. Notably, patterned expression of RA signaling components was also found in humans, suggesting that RA also plays a role in setting up the human fovea.
Keywords: high-acuity area; HAA; fovea; development; retinoic acid; RA; Fgf8; photoreceptor; chick; human
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"We're suggesting that removing retinoic acid at the right time, adding Fgf8 or otherwise manipulating these two molecules may allow generation of fovea [in a petri dish]"
Connie Cepko PhD. Image Credit: Harvard Medical School