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Mouse Study Reveals Mammalian Genetic ‘Compass’ Helps Sensory Cells for Hearing Find Their Bearings

May 1, 2003

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Two genes in mice help determine the direction in which auditory hair cells, small sensory cells in the inner ear that are critical for hearing, become oriented, according to a study published in the April 30 advance online issue of Nature. The discovery is the first to link a mammalian gene to the reason cells "know" to grow in a certain direction, a mechanism referred to as planar cell polarity. Another example of planar cell polarity in mammals is the unidirectional growth of hair follicles. The study was conducted by researchers at the National Institute on Deafness and Other Communication Disorders (NIDCD), Rockville, Md., in collaboration with other researchers located primarily at the National Cancer Institute, Frederick, Md.

A person's ability to hear depends largely on the actions of stereocilia, hairlike extensions jutting upward from the top of each hair cell in a bundle with a crescent, or "V" shape. Sound vibrations traveling into the cochlea, the snail-shaped part of the inner ear where hair cells reside, are converted into electrical signals by the stereocilia as they bend. The electrical signals, in turn, travel along the auditory nerve to the brain, where they can be interpreted.

"Hair cells are unique because they're directionally sensitive," said Dr. Matthew Kelley, Acting Chief of the Section on Developmental Neuroscience in the laboratories of the NIDCD, and one of the authors of the study. "If the stereocilia bundle is bent towards the vertex of the crescent shape, then the hair cells will generate a signal, but if the bundle is bent in any other direction, no signal will be generated. We wanted to find out how the hair cell knows to point its stereocilia bundle in the right direction."

Using confocal and scanning electron microscopy, the researchers examined hair cells from mouse embryos containing one of two genetic mutations. They then compared the stereocilia bundles from those mice with their healthy "wild-type" littermates. The first gene, Vangl2, is the mouse equivalent of a gene that helps regulate cellular orientation in the fruit fly. Mice that contain two copies of the mutated version of Vangl2 (homozygous) and no copies of the normal version of Vangl2 have an open neural tube throughout the hindbrain and spinal region and usually die shortly before or at birth. The second gene, Scrb1, is the mouse equivalent of the fruit fly's scribble gene. Although the scribble gene does not play a direct role in cellular orientation in the fruit fly, mice that are homozygous for its mutation exhibit defects in the neural tube that are comparable to the Vangl2 mutants.

In the wild-type mice, the "V"-shaped stereocilia bundles on the single row of inner hair cells, which are responsible for transmission of the auditory nerve signal, and the three rows of outer hair cells, which help to amplify sounds, were all pointing away from the auditory nerve. However, in mice that possessed two copies of the Vangl2 mutation, stereocilia bundles were pointing in many different directions, with some bundles rotated by as much as 180 degrees, although the bundle's overall structure appeared normal. Similar results were found for mice with two copies of the Scrb1 gene, though to a lesser degree. While both inner and outer hair cells were misoriented for homozygous Vangl2 mutants, only the second and third rows of the outer hair cells were misoriented for homozygous Scrb1 mutants.

The researchers further noted that mice carrying one copy of the Vangl2 mutation and one copy of the Scrb1 mutation demonstrated orientation defects on both inner and outer hair cells that were similar to mice with two copies of the Vangl2 mutation, a finding that led them to conclude that the two genes interact to influence polarity.

How the genes interact is still open to question, however. One hypothesis put forth by these scientists is that the proteins encoded by the two genes combine to help direct the movement of each hair cell's kinocilium. The kinocilium is a structure composed of microtubules whose movement dictates the location of the vertex of the "V"-shaped stereocilia bundle during development. And in fact, movement of the kinocilium was significantly altered in homozygous Vangl2 mutants.

"This makes sense because the kinocilium must move to the correct location in the cell to influence the orientation of the rest of the stereocilia bundle," said Dr. Mireille Montcouquiol, first author on the paper and a Research Fellow in Dr. Kelley's laboratory.

According to Montcouquiol, the next step will be to investigate the biochemical interactions that are taking place between the proteins coded for by the two genes, as well as locating other possible mutations that may contribute to hair cell orientation. Other questions include learning how Vangl2 determines where the kinocilium should move in the cell as well as how it pushes or pulls the stereocilia into the proper orientation. Moreover, the group is interested in discovering how misorientation of the stereocilia bundles affects overall hearing ability in mammals.

The only other study that links a mammalian gene to planar cell polarity is described in the June 1 issue of Development. Research fellow Dr. Alain Dabdoub and colleagues, also in NIDCD's Section on Developmental Neuroscience, reported that Wnt7a, a secreted protein in mice, may also play an important role in signaling the orientation of stereocilia in outer hair cells.

The National Institute on Deafness and Other Communication Disorders is one of the Institutes of the National Institutes of Health, within the Department of Health and Human Services. NIDCD supports and conducts research and research training on the normal processes and diseases and disorders of hearing, balance, smell, taste, voice, speech, and language that affect millions of Americans.


Last Updated Date: 
May 1, 2003