The Skaggs Institute
for Chemical Biology
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
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.