New Study Examines Role Of Proteins In Ensuring Precision

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, Ph.D., 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
Both types of hair cells 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.
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
The production of hair cells in the cochlea during embryo development is a highly organized and
the intricate process involving precise timing and location.
The process begins when immature cells at the outer cochlea transform into fully formed hair
From the outer cochlea, the orderly transformation then proceeds like a wave along with the internal
the 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?"
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
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
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.
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 are so precisely timed during development that any
disturbance can negatively affect the organization of the cochlea.
Doetzlhofer suggests that the findings could lead to new treatments for restoring hearing that
becomes impaired due to the loss of hair cells.


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