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The Skaggs Institute
for Chemical Biology

Scientific Report 2008

Auditory Perception and Hearing Impairment: From Mouse Models to Human Genetic Disease

U. Mü;ller, C. Barros, F. Conti, H. Elledge, S. Franco, N. Grillet, S. Harkins-Perry, P. Kazmierczak, I. Martinez-Garay, R. Radakovits, C. Ramos, A. Reynolds, M. Schwander, =S. Webb, W. Xiong

Mechanosensation, the transduction of mechanical force into an electrochemical signal, allows living organisms to detect touch, hear, register movement and gravity, and sense changes in cell volume and shape. The hair cells of the mammalian inner ear are the principal mechanosensors for the detection of sound and head movement. We identify and study genes that control the development and function of hair cells. We are particularly interested in the molecules that form the mechanotransduction machinery of these cells. We also analyze the mechanisms that establish neuronal connections between the auditory sense organs and the cerebral cortex and the formation of cell layers and neuronal circuits within the cerebral cortex.

Molecular Composition Of The Mechanotransduction Machinery In Hair Cells

The mechanically sensitive organelle of a hair cell is the hair bundle, which consists of dozens of stereocilia that project from the apical cell surface. Mechanotransduction channels are localized close to the tips of stereocilia. Tip-links, extracellular filaments that connect the tips of neighboring stereocilia and are visible by electron microscopy, are thought to transmit sound-induced tension force onto the transduction channels. The molecular identity of most components of the mechanotransduction complex is still largely unknown.

To identify genes that control hair cell function, such as the transduction channel and the tip-links, we use genetic approaches. Approximately 1 child in 1000 children is born deaf, and a large part of the human population experiences age-related hearing loss. Many forms of hearing loss are of genetic origin, and mutations in more than 400 genes cause deafness. Recently, we discovered that some of the genes linked to Usher syndrome, the leading cause of deaf-blindness in humans, may encode components of the mechanotransduction machinery in hair cells. Using mouse model systems, we have shown that the Usher syndrome proteins cadherin 23 and protocadherin 15 interact to form tip-links in hair cells.

Intriguingly, some of the mutations in the genes for cadherin 23 and protocadherin 15 that cause deafness in humans disrupt interactions between the 2 proteins. Others leave interactions intact and probably change the mechanical properties of tip-links and affect the mechanotransduction process. Currently, we are defining the biophysical properties of cadherin 23 and protocadherin 15, investigating whether other genes linked to deafness encode components of the mechanotransduction machinery, and generating mouse models for diseases that affect hair cell function in mechanotransduction.

Mouse Models Of Deafness

Deafness has a profound effect on the quality of life of the affected individuals, yet few promising therapeutic approaches exist to help these individuals. To identify genes that control auditory perception and to provide animal models for the human disease, we carried out a genetic screen in mice. Using N-ethyl-N-nitrosourea, we introduced point mutations in the germ line of mice. Using phenotypic screens, we identified more than 20 mouse lines in which the mice inherit hearing defects as recessive traits. We have mapped many of the mutations to chromosomal intervals and have used DNA sequencing to identify mutations in single genes that cause some of the hearing defects.

All of the genes that we have identified so far are expressed in hair cells. One of the genes encodes the unconventional motor protein myosin VIIa. Interestingly, mutations in myosin VIIa have been linked to Usher syndrome in humans. Our phenotypic analysis of the mice with the myosin VIIa mutation indicated that the mutation affects expression of the protein differentially in the ear and retina and provides a molecular explanation of why some mutations in the human gene for myosin VIIa affect the function of the protein in the ear and retina, whereas other mutations only affect the function of myosin VIIa in the ear. A mutation in a second mouse line maps to a gene that encodes an enzyme important for the control of neurotransmitter levels. We have identified a similar mutation in human families with deafness.

Our studies show that genetic screens in mice are powerful tools for identifying mutations that control the function of hair cells and that mutations in mice can serve as models for deafness in humans. In future studies, we will define the structure and function of the normal and pathogenic variants of the involved proteins to gain insights into disease mechanisms at the cellular, molecular, and anatomic level.


Du, X., Schwander, M., Moresco, E.M., Viviani, P., Haller, C., Hildebrand, M.S., Pak, K., Tarantino, L., Roberts, A. Richardson, H., Koob, G., Najmabadi, H., Ryan, A.F., Smith, R.J., Mü;ller, U., Beutler, B. A catechol-O-methyltransferase that is essential for auditory function in mice and humans. Proc. Natl. Acad. Sci. U. S. A. 105:14609, 2008.

Mü;ller, U. Cadherins and mechanotransduction by hair cells. Curr. Opin. Cell Biol. 20:557, 2008.

Mü;ller, U., Gillespie, P. Silencing the cochlear amplifier by immobilizing prestin. Neuron 58:299, 2008.


Ulrich Müller, Ph.D.

Müller Web Site