Zebrafish Help Scientists Understand Hearing Restoration

Cell lineages in the inner ear: Schematic illustrating pseudotime cell ordering in the adult zebrafish inner ear. Inner ear HC lineage populations are colored according to their cluster membership and shown in pseudotime order. (A regulatory network of Sox and Six transcription factors initiate a cell fate transformation during hearing regeneration in adult zebrafish)

A new U.S. genomics study has found a unique set of proteins that allow Zebrafish to restore hearing after injury through the regeneration of hair cells, a finding that may pave the way to new treatments for human deafness.

While the loss of hair cells—hearing receptors in the inner ear—is irreversible in humans, many animals such as fish, amphibians, and birds can regenerate hair cells. As mammals produce hair cells during embryo formation in utero, the ear’s hair cells lost after birth are virtually irreplaceable, resulting in permanent hearing loss, deafness, or vestibular disorders.

By building understanding of the genes that enable hearing restoration in the zebrafish, a species that shares more than 70 percent of its genes with humans, scientists seek to inform the development of treatments for deafness in people.

“Humans and other mammals are born with a set number of hair cells that are slowly lost through aging and trauma. However, some animals, such as zebrafish, can regenerate hair cells and recover hearing after injury,” said Shawn Burgess, senior investigator at the Translational and Functional Genomics Branch of the National Human Genome Research Institute (NHGRI), and one of the study’s researchers.

The study found that transcription factors—a network of proteins with the ability to switch genes on and off—are the key to hair cell regeneration. These transcription factors bind to enhancer sequences to express the genes responsible for restoring hearing, much like how a key activates an ignition switch to start a car.

“Our study identified two families of transcription factors that work together to activate hair cell regeneration in zebrafish, called Sox and Six transcription factors,” explained Erin Jimenez, one of the NHGRI study’s lead researchers.

When hair cells begin to die in Zebrafish, surrounding support cells begin replicating and transform into hair cells to take the place of dead hair cells, regenerating hearing. Together, the Sox and Six transcription factors are responsible for turning support cells into hair cells.

“We have identified a unique combination of transcription factors that trigger regeneration in zebrafish. Further down the line, this group of zebrafish transcription factors might become a biological target that may lead to the development of novel therapy to treat hearing loss in humans,” Jimenez said.

However, there are also other factors responsible for converting support cells into hair cells, and it remains unknown where the genes coding for these factors lie within the genome, and how exactly these genes turn on.

The study, led by researchers at the NHGRI, was published in August 2022 in Cell Genomics.