Insights into Neurodegenerative Diseases and Pest Control

A recent USC Stem Cell study published in Proceedings of the National Academy of Sciences (PNAS) has identified key gene regulators that enable certain animals, like fish and lizards, to naturally regenerate their hearing. These findings could guide future efforts to regenerate sensory hearing cells in humans with hearing loss and balance disorders.

Led by First Author Tuo Shi and Co-Corresponding Authors Ksenia Gnedeva and Gage Crump from USC's Keck School of Medicine, the study focused on two types of inner ear cells: supporting cells, which create an environment conducive to sensory cell growth, and sensory cells, which detect sound.

In regenerative species like zebrafish and green anole lizards, supporting cells can transform into new sensory cells after injury. However, this ability is absent in mammals, including humans and mice. The study explored how genes typically active in sensory cells are reactivated in the supporting cells of regenerative species.

The researchers analyzed the genome structure in the inner ear cells of zebrafish and green anole lizards, comparing it to non-regenerative species like mice. According to Gage Crump, “By comparing two different regenerative vertebrates, zebrafish and lizards, to non-regenerative vertebrates such as mice, we found something fundamental to the way sensory cells can be replaced to restore hearing in some vertebrates.”

They identified a class of DNA control elements, called “enhancers,” which promote the production of ATOH1, a protein crucial for forming inner ear sensory cells. Using CRISPR, they deleted five enhancers in zebrafish, hindering both the development of sensory hearing cells and their ability to regenerate after injury. Crump noted, “In the past, deletion of individual enhancers most often does not have much of an effect. But by targeting all five enhancers in zebrafish, we discovered their critical role in both development and regeneration.”

Interestingly, the genetic deletions only affected the inner ear cells in zebrafish, leaving similar sensory cells in their lateral line organ, which senses water flow and pressure, unaffected.

The study also found that mice have similar enhancers active during embryonic development, but only regenerative species like fish and lizards maintain these enhancers in an open state into adulthood, enabling supporting cells to replace damaged sensory cells.

“What we have found is that sister cell types in regenerative vertebrates maintain open enhancers from development into adult stages, thus allowing these related cells to replace each other following damage,” Crump explained. “In the future, targeted strategies to open up these enhancers in the human inner ear could be used to boost our natural regenerative abilities and reverse deafness.”