Hippo Pathway Blocks Retinal Regeneration

A new discovery opens the possibility of restoring vision loss by activating the retina’s ability to regenerate. In a study published today in the journal Cell Reports, researchers reveal that the mammalian retina has a regenerative capacity that is kept dormant by a cellular mechanism called the Hippo pathway.

“Damage to the retina can lead to irreparable loss of vision in humans and other mammals because their retinas do not regenerate,” says senior author Ross A. Poché of Baylor College of Medicine. “However, other animals such as zebrafish can reverse blindness thanks to specialized cells in the retina called Müller glial cells. When the retina is damaged, Müller glial cells proliferate and differentiate into the lost retinal neurons, effectively replacing injured cells with fully functional ones.”

Although Müller glial cells in injured mammalian retina do not restore vision as their counterpart in zebrafish do, other researchers have shown that, when the mammalian retina is injured, a small subset of Müller glial cells takes the first steps needed to enter the proliferation cycle. “But this attempt to proliferate is transient; after acquiring some of the cell markers, the cells shut off,” Poché says. “These observations suggested that the mechanism that drives cell repair in zebrafish also might be present in mammals but is actively suppressed.”

The researchers focused their attention on the Hippo pathway, a network of molecular events that contributes to organ growth during development and to heart tissue regeneration after myocardial infarction. The researchers have previously shown that the Hippo pathway acts like a ‘break’ on cardiomyocyte proliferation by inhibiting another pathway called YAP.

In the present study, the team first determined that the Hippo pathway is expressed in mammalian Müller glial cells. Next, they investigated whether altering the Hippo pathway in these cells would affect their ability to proliferate. Creating a malfunctioning Hippo pathway by eliminating two of its molecular steps resulted in modest cell proliferation. And when the researchers genetically engineered Müller glial cells to carry a version of YAP called YAP5SA that is impervious to the inhibitory influence of Hippo, the cells showed major proliferation and acquired a progenitor cell identity. A small subset even showed signs of spontaneous differentiation into retinal neurons.

“Our next step is to develop a strategy to guide proliferating Müller glial cells into differentiation pathways leading to retinal cells capable of restoring vision,” Poché says.