For decades, biomedical engineers and doctors have turned to the retina of the lab mouse as the ideal model for understanding how neurons connect to form circuits in the brain. But as a model for vision and vision-related diseases, mice simply aren’t a a good choice.
The problem, says Joshua Sanes, a professor at Harvard’s Center for Brain Science, is that they lack a fovea which is a small, specialized area in the retina of concentrated cones. It makes sharp central vision possible. Among mammals, only primates have a fovea.
The fovea has been well-studied for decades. Researchers have demonstrated both functional and structural specialization in foveal cells, but the mechanisms that give rise to the differences between the fovea and the peripheral retina have remained a mystery.
To begin unraveling that mystery, a team of researchers led by Sanes used high-throughput genetic sequencing to create the first cellular atlas of the primate retina. They found that although the fovea and peripheral retina share most of the same types of cell, they are found in different proportions in each region.
The atlas will provide researchers with an important foundation to build on as they seek to discover how vision works in primates, including humans, and how it can be disrupted by disease.
To create the cellular atlas, Sanes and his colleagues began with 165,000 cells collected from the retinas of macaques, about half of them foveal and half peripheral. The team used genetic tools to separate them into their various types, identifying 65 to 70 separate types in both parts of the eye.
The results produced both good and bad news.
The good news, Sanes says, is that the team came up with ideas about what makes the fovea special. “About 90% of the cell types are shared,” Sanes says. “But what is more telling is that the two types express a lot of different genes. We believe looking at those genes will help us explain a lot of the functional differences between cells in the fovea and the periphery.”
The bad news is that when the team tried to find mouse equivalents of the main cell type that sends a message from the fovea to the brain (called the “midget ganglion cell” for its small size) they failed.
“Unfortunately, ‘midgets’ are the vast majority of foveal ganglion cells,” Sanes says. “We’d hoped to find the mouse equivalent of those cells so we could study them using all the tools we’ve already developed, but we didn’t.”
Armed with their cellular atlas, Sanes and his colleagues turned to nearly 200 genes implicated in blinding diseases and found that some, particularly those associated with macular degeneration and diabetic macular edema, are expressed selectively in foveal cells, a tantalizing clue for why such diseases primarily affect the fovea: The macula is a slightly larger region of the retina with the fovea at its center, so “this pattern makes sense,” says Sanes.
“For example, we found one macular-degeneration-susceptibility gene is expressed at higher levels in foveal rods and cones than in peripheral rods and cones,” Sanes says. “That may be related to the fact that it’s a macular disease. Similarly for diabetic macular edema we found two susceptibility genes expressed at higher levels in the blood vessels in the fovea than in the periphery.” Macular degeneration and diabetic macular edema are among the leading causes of blindness in the U.S. and the world.
“We also took those genes back to the mouse cellular atlas,” Sanes continued. “In many cases they either weren’t expressed or were expressed in different cells. That suggests that, for at least some of these diseases, looking at how a gene acts in mice may not be very telling, because it may not be expressed in the same cells.”
Going forward, Sanes said, the cellular atlas could serve as a valuable resource for studies focused on specific diseases and for basic science questions.
“On the disease side, just by having this knowledge we may come up with better treatments,” Sanes said. “This could also be a foundation for looking at pathological material. We are collaborating with people who have saved eye specimens over the years for various purposes. So we could test hypotheses, see if perhaps people with glaucoma are missing a certain cell type or the expression of a gene is too low or too high.
“On the basic research side,” he continues, “we can take a gene we may think plays a role in the cells’ physiological differences and put it in a mouse cell to see if it changes that cell’s properties. This will give us a head start as we try to answer these kinds of questions.”