A New Notion of How We Hear Takes Root

Although scientists are still working out the fine details of how we hear, they at least thought they had most of the major players nailed down. Now, new research published in the May 28 issue of the journal Cell shines a light on a cell structure in the inner ear that is more critical to hearing than anyone would have first guessed.

Our ability to hear relies on sound vibrations traveling from the outer ear past the eardrum through the middle ear to the sensory cells inside the inner ear—called hair cells—that have bundles of stiff hair-like projections—called stereocilia—jutting from their tops. When stimulated by sound vibrations, the stereocilia initiate an electrical signal that travels to the brain, where it is transformed into sound sensation.

But an international research team led by scientists from the National Institute on Deafness and Other Communication Disorders (NIDCD) has found that a structure at the base of the stereocilium is also critical to the hearing process. The structure, called the rootlet, is a short connector piece between a stereocilium and a hair cell, extending a short distance into each component like a toothpick that connects the narrow end of a dill pickle (the stereocilium) to a large chunk of cheese (the hair cell).

"Just like stereocilia, the rootlet consists of the protein actin, but it's a denser structure than the stereocilium. Nobody knew precisely what it is made of and what its function is," says NIDCD geneticist Thomas Friedman, Ph.D., senior researcher on the study. "Obviously if you see something extending down into one structure, then up into another one, you think of it as an anchor. And it turns out that's true, but it does much more than that, and that actually surprised us."

In earlier studies, members of Dr. Friedman's team had found that mutations in a gene called TRIOBP(pronounced tree-oh BP) are associated with a type of hereditary deafness in humans called DFNB28. In this study, the team discovered that not only is the protein TRIOBP critical for the formation of the rootlet, but stereocilia that lack rootlets will not be able to function properly and degenerate.

The scientists used specially marked antibodies that bind to TRIOBP to show where it's located in the mouse inner ear, and saw that three key variants of the protein are located in the rootlet. In addition, they discovered that the protein was located primarily around the outside of the actin filaments that form the rootlet.

Next, the team wanted to see how TRIOBP interacted with actin filaments. They purified one of the human TRIOBP variants and mixed it into a solution with actin filaments, similar to those that compose stereocilia. When they centrifuged the two substances together at high speeds, they found that the TRIOBP and actin formed clumps, indicating that the protein binds with the actin filaments. When they examined the bundles under an electron microscope, they saw that the actin filaments were tightly packed—as dense as those found in stereocilia rootlets and much denser than the actin filaments found in the body of a stereocilium.

Finally, in a mouse model, the scientists removed a short but functionally important stretch of the gene that corresponds to the region of the humanTRIOBP gene where human deafness mutations are found. Indeed, without functional TRIOBP, the rootlets did not form and the mice were deaf. Stereocilia that lacked rootlets were found to be more flexible and fragile than those with rootlets, which could explain why deafness occurs in mice lacking functional TRIOBP and in humans with mutations in the TRIOBP gene.

The researchers propose that TRIOBP forms a rootlet by winding itself very tightly around the stereocilia's actin filaments that insert into the hair cell. The rootlet gives the stereocilia greater rigidity and durability yet flexibility, which is required for the stereocilia to function properly.

Other organizations whose scientists contributed to the study are the National Heart, Lung and Blood Institute;National Institute of Diabetes and Digestive and Kidney Diseases;University of Sussex, England;University of Kentucky, Lexington;University of Punjab, Lahore, Pakistan;and Northwestern University, Chicago.