The Skaggs Institute
for Chemical Biology
Auditory Perception and Hearing Impairment: From Mouse Models to Human Genetic Disease
U. Müller, C. Barros, R. Belvindrah, F. Conti, S. Franco, N. Grillet, S. Harkins-Perry, P. Kazmierczak, I. Martinez-Garay, Y. Pavlova, R. Radakovits, C. Ramos, A. Reynolds, A. Sczaniecka, M. Schwander, S. Webb, W. Xiong
organs convert signals such as light and sound into electrical impulses that are
processed by the nervous system to create an internal representation of our surroundings
and to elicit appropriate behavioral responses. Of all the sensory systems in humans,
the auditory system is the least well understood at the molecular level. We identify
and study genes that control the function of the auditory sense organ of mammals.
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 cortex.
Mechanoelectrical Transduction and Hearing: Human Genetics
to perceive sound is critically dependent on mechanoelectical transduction (MET),
the conversion of mechanical force into electrical signals. The auditory mechanoreceptor
cells in mammals are the hair cells of the cochlea. The architectural features of
the cochlea and the properties of the hair cells are essential for encoding time-variant
frequency components of sound as spatiotemporal arrays of neural discharge that
provide the sense of hearing. 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. MET 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 MET channel. The molecular identity of most components of the MET
complex is still unknown.
genes that control hair cell function, such as the MET channel and the tip-links,
we use genetic approaches. Approximately 1 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. Some of the affected genes have been identified and may encode components
of the MET complex in hair cells. Two of the genes linked to deafness encode cadherin
23 and protocadherin 15, members of the cadherin superfamily of cell adhesion molecules.
Both genes are expressed in hair cells, and our recent studies showed that cadherin
23 and protocadherin 15 interact to form tip-link filaments. Our findings defined
the first components of the MET complex in hair cells at the molecular level and
provide tools for identifying additional components of the MET complex that likely
interact with cadherin 23 and protocadherin 15, such as mechanically gated ion channels.
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 likely change the mechanical properties of the tip-link and affect the
MET process. We classify these diseases as MET diseases.
The Molecular Pathogenesis of Deafness: Animal Models for the Human Disease
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
19 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 the genes
that we have identified so far are expressed in hair cells. Some of the genes encode
proteins with known functions, such as myosin motor proteins. Others belong to entirely
new gene families that have not been studied before. Several of the genes identified
in our screen had already been linked to deafness, but we also identified mutations
in genes that had not. One of these genes encodes the protein pejvakin. Our studies
indicate that pejvakin is expressed in hair cells and is required for their function.
We have screened human families with deafness for mutations in the pejvakin gene
and have identified a mutation in an Iranian family that is inherited as a recessive
show that genetic screens in mice are powerful not only for identifying genes that
control the function of hair cells but also for linking genes to disease in humans.
In future studies, we will define the structure and function of the normal and pathogenic
variants of the proteins to gain insights into disease mechanisms at the cellular,
molecular, and anatomic levels.
Herr, D., Grillet, N., Schwander, M., Rivera, R., Müller, U., Chun, J. Sphingosine 1-phosphate signaling is required for maintenance of hair cells mainly via activation
of S1P2. J. Neurosci. 27:1474, 2007.
Kazmierczak, P., Sakaguchi, H., Tokita, J., Wilson-Kubalek, E.M., Milligan, R.A., Müller, U., Kachar B. Cadherin
23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 449:87, 2007.
Schwander, M., Sczaniecka, A., Grillet, N., Bailey, J.S., Avenarius, M., Najmabadi, H., Steffy, B.M., Federe, G.C., Lagler, E.A., Banan, R., Hice, R., Grabowski-Boase, L., Keithley,
E.M., Ryan, A.F., Housley, G.D., Wiltshire, T., Smith, R.J.H., Tarantino, L.M., Müller, U. A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function.
J. Neurosci. 27:2163, 2007.
Senften, M., Schwander, M., Kazmierczak, P, Lillo, C., Shin, J.B., Hasson, T., Géléoc, G.S.G., Gillespie, P.G., Williams, D., Holt, J.R., Müller, U.
Physical and functional interaction between protocadherin 15 and myosin VIIa in mechanosensory hair cells. J. Neurosci. 26:2060, 2006.