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Scientific Report 2008

Cell Biology

Auditory Perception and Neuronal Circuit Formation: From Mouse Models to
Human Genetic Disease

U. Müller, C. Barros, F. Conti, H. Elledge, S. Franco, N. Grillet, C. Gillsanz, S. Harkins-Perry, P. Kazmierczak, I. Martinez-Garay, R. Radakovits, C. Ramos, M. Schwander, S. Webb, W. Xiong

A fundamental unresolved question in biology is how the nervous system in humans creates an internal representation of the external world. Sense

Organs convert signals such as light and sound into electrical impulses that are processed by the nervous system to create a reflection of the surroundings and to elicit appropriate behavioral responses. Selective pressures during evolution have shaped the human genome and optimized sense organs and neuronal circuits for their tasks. 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.

Auditory Perception

The ability to perceive sound is critically dependent on mechanoelectrical 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 (Fig. 1). 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.
Fig. 1. Scanning electron microscopy image of the mammalian cochlea. Hair cells are arranged in 3 rows of outer hair cells (to the left) and 1 row of inner hair cells (to the right). Each hair cell contains a bundle of stereocilia (orange) at the apical surface that form the mechanically sensitive organelle of the cell.

We are identifying genes that control hair cell function, such as those for the MET channel and the tip-links. 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. 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 studies indicate that cadherin 23 and protocadherin 15 interact to form tip-link filaments. Thus, we have defined the first components of the MET complex in hair cells at the molecular level. Our findings provide tools for identifying additional components of the MET complex that likely interact with cadherin 23 and protocadherin 15.

In an alternative approach to studies of auditory perception, 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 of 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 previously. Intriguingly, all the genes identified in our screen are also linked to deafness in humans. Therefore, the screen is powerful not only for identifying genes that control the function of hair cells but also for providing animal models for the human disease.

Neuronal Circuit Formation

Sensory information is ultimately relayed to specific areas of the CNS such as the auditory and visual cortex. Although the cortex is divided into functional domains, the overall organization of all cortical structures is similar and consists of cell layers that connect to each other to form neuronal circuits. The mechanisms that lead to the establishment of neuronal circuits in the cerebral cortex are mostly unknown.

Using genetic tracing studies, we are visualizing neuronal connections that are essential for the processing of auditory signals. In addition, we are defining the genes and mechanisms that lead to the formation of neuronal cell layers. Our studies have already shown that extracellular matrix receptors of the integrin family have important functions in the formation of cell layers and the control of synaptic function. We are currently using genomic approaches to search for novel genes that specify cortical layers and lead to neuronal circuit formation. We are also participating in a large-scale effort by the National Institutes of Health to generate a panel of mice useful for the perturbation of gene function in defined areas of the CNS, including defined neuronal subtypes in cortical cell layers.


Belvindrah, R., Graus-Porta, D., Goebbels, S., Nave, K.-A., Müller, U. β 1 integrins in radial glia but not in migrating neurons are essential for the formation of cell layers in the cerebral cortex. J. Neurosci. 27:13854, 2007.

Conti, F.J., Felder, A., Monkley, S., Schwander, M., Wood, M.R., Lieber, R., Critchley, D., Müller, U. Progressive myopathy and defects in the maintenance of myotendinous junctions in mice that lack talin 1 in skeletal muscle. Development 135:2043, 2008.

Du, X., Schwander, M., Moresco, E.M., Viviani, P., Haller, C., Hidebrand, M.S., Pak, K., Tarantino, L., Roberts, A., Richardson, H., Koob, G., Najmabadi, H., Ryan, A.F., Smith, R.J., Müller, 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.

Müller, U. Cadherin and mechanotransduction by hair cells. Curr. Opin. Cell Biol. 20:557, 2008.

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

Nishimune, H., Valdez, G., Jarad, G., Moulson, C.L., Müller, U., Miner, J.H., Sanes, J.R. Laminins promote postsynaptic maturation by an autocrine mechanism at the neuromuscular junction. J. Cell Biol. 182:1201, 2008.

Wang, H.V., Chang, L.W., Brixius, K., Wickström, S.A., Montanez, E., Thievessen, I., Schwander, M., Müller, U., Bloch, W., Mayer, U., Fässler, R. Integrin-linked kinase stabilizes myotendinous junctions and protects muscle from stress-induced damage. J. Cell Biol. 180,1037, 2008.


Ulrich Müller, Ph.D.

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