A new genetic study in mice has identified two proteins that help organize the development of the hair cells that pick up sound waves in the inner ear.

Researchers at the Johns Hopkins School of Medicine in Baltimore, MD, believe that their findings could hold the key to reversing hearing loss that arises from damaged hair cells. A recent paper in the journal eLife gives a full account of the investigation.

"Scientists in our field," says Angelika Doetzlhofer, PhD, an associate professor of neuroscience at Johns Hopkins, "have long been looking for the molecular signals that trigger the formation of the hair cells that sense and transmit sound."

"These hair cells are a major player in hearing loss, and knowing more about how they develop will help us figure out ways to replace hair cells that are damaged," she adds.

In mammals, the ability to hear relies on two types of cell that detect sound: inner and outer hair cells. Both types of hair cell line the inside of the cochlea, a spiral-shaped hollow in the inner ear. The hair cells form a distinct pattern comprising three rows of outer cells and one row of inner cells. The cells sense sound waves as they travel down the shell-like structure and convey the information to the brain.

Development and loss of hair cells

Problems with hair cells and the nerves that connect them to the brain are responsible for more than 90% of hearing loss.

Most mammals and birds have the ability to automatically replace lost or damaged hair cells, but this does not happen in humans. Once we lose our hair cells, it seems that hearing loss is irreversible.

The production of hair cells in the cochlea during embryo development is a highly organized and intricate process involving precise timing and location. The process begins when immature cells at the outer cochlea transform into fully formed hair cells. From the outer cochlea, the orderly transformation then proceeds like a wave along the internal lining of the spiral until it reaches the innermost region.

Although scientists have uncovered much about hair cell formation, the molecular signals that control the "precise cellular patterning" have remained unclear.

How do the signals make the right part of the process happen at the correct time to "promote auditory sensory differentiation and instruct its graded pattern?"

Signaling proteins and gradients

To try to answer the question, Doetzlhofer and her colleagues studied cochlear development in mouse embryos. They investigated signaling proteins that play a role in hair cell formation in the developing cochlea. Two of the proteins that the researchers investigated caught their attention: Activin A and follistatin.

They saw how the levels of the two proteins changed during the transformation of precursor cells into mature hair cells along the inside of the cochlear spiral. The protein levels appeared to vary according to the timing and location of the development pattern.

Activin A levels were low at the outermost part of the cochlea when immature cells started to develop into hair cells and high at the innermost part of the spiral, where immature cells had not yet begun to transform.

The authors refer to such high-to-low protein level changes as signaling gradients. "Signaling gradients play a fundamental role in controlling growth and differentiation during embryonic development," they note.

The two proteins 'work in opposite ways'

While the Activin A signaling gradient went one way, moving in a wave that went inward, the follistatin signaling gradient went the other way, like a wave moving outward.

"In nature, we knew that Activin A and follistatin work in opposite ways to regulate cells," Doetzlhofer explains. These findings seem to suggest that the two proteins control the precise and delicate development of hair cells along the cochlear spiral by balancing each other.

Further investigation using both normal and genetically engineered mice confirmed this notion. Increasing Activin A in the cochleas of normal mice made hair cells mature too soon. Conversely, hair cells formed too late in genetically engineered mice that either produced too much follistatin or produced no Activin A at all. The result was a disorganized pattern of hair cells on the inside of the cochlear spiral.

"The action of Activin A and follistatin is so precisely timed during development that any disturbance can negatively affect the organization of the cochlea."

—Angelika Doetzlhofer, PhD

Doetzlhofer suggests that the findings could lead to new treatments for restoring hearing that becomes impaired due to the loss of hair cells.