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  • Review Article
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Quiet as a mouse: dissecting the molecular and genetic basis of hearing

Nature Reviews Genetics volume 9, pages 277–290 (2008)Cite this article

Key Points

  • A combination of genetic, biochemical, ultrastructural and physiological studies of mouse mutants has made crucial contributions to the understanding of the molecular mechanisms of hearing.

  • The similarities in auditory structure and physiology between mouse and human, along with the relatively close evolutionary relationship of these two genomes, make the mouse a useful model system for the study of the functional genetics of the auditory system.

  • A comprehensive toolkit is available for manipulating the mouse genome, and various mouse mutagenesis approaches, both gene driven and phenotype driven, are being used to generate and investigate new mouse lines with hearing impairment. In addition, a substantial number of spontaneous mutants have been discovered and catalogued over the years.

  • Stereocilia emerge from the apical surface of the hair cell in the inner ear and are the site of auditory transduction. Mouse mutants have had a seminal role in deciphering the mechanisms behind the growth of stereocilia and the maintenance of the cohesion of the stereocilia bundle that is crucial for auditory function.

  • Various mouse deaf mutants that affect stereocilia growth have uncovered a number of proteins. These include the whirlin protein, which seems to act as a scaffold for a complex that is involved in actin polymerisation and stereocilia elongation.

  • Cohesion of the stereocilia bundle is affected in a number of other mouse deaf mutants; the underlying genes have been identified and include another PDZ scaffold protein, harmonin. Mutations in the corresponding human genes lead to Usher syndrome, characterized by hearing loss and retinitis pigmentosa.

  • An 'Usher interactome' that is responsible for bundle cohesion has been revealed through numerous techniques: the identification of genes that underlie stereocilia-bundle defects; investigations into the localization of these proteins within the developing stereocilia; and studies to determine interactions between the constituent molecules.

  • Whirlin is a component of the Usher interactome, indicating that the processes of stereocilia growth and stereocilia cohesion share common components; it also suggests that evolution has been parsimonious in developing molecular processes within stereocilia.

  • The localization of protein members of the Usher interactome reveals that the two scaffold proteins, harmonin and whirlin, have roles in organizing different components of the interactome that are in turn involved in organizing different classes of interstereocilial links.

  • Presbycusis, late-onset hearing loss, is a multifactorial disease for which there has been little progress in identifying the underlying genes. However, mouse models are making a contribution to identifying loci. Mouse mutant studies have revealed that different mutations in the same gene can lead to both early-onset and late-onset deafness, although it is likely that the pathological processes in presbycusis will often be distinct from profound early-onset deafness and will involve different classes of loci.

  • Mouse mutagenesis continues to reveal various novel deafness models, such as that of otitis media, and mouse genetics can be expected to continue to offer a rich source of insight into the molecular mechanisms of hearing.

Abstract

Mouse genetics has made crucial contributions to the understanding of the molecular mechanisms of hearing. With the help of a plethora of mouse mutants, many of the key genes that are involved in the development and functioning of the auditory system have been elucidated. Mouse mutants continue to shed light on the genetic and physiological bases of human hearing impairment, including both early- and late-onset deafness. A combination of genetic and physiological studies of mouse mutant lines, allied to investigations into the protein networks of the stereocilia bundle in the inner ear, are identifying key complexes that are crucial for auditory function and for providing profound insights into the underlying causes of hearing loss.

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Figure 1: Mammalian outer, middle and inner ear.
Figure 2: Protein complexes essential for stereocilia growth.
Figure 3: Stereocilia bundle cohesion and stability — insights from mouse models.
Figure 4: A visualization of the Usher protein network based on mouse genetics and protein interaction studies.
Figure 5: Mouse models of otitis media.

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Acknowledgements

This work was supported by the Medical Research Council and FP6 Integrated Project, EUROHEAR, LSHG-CT-2004-512063.

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Authors and Affiliations

  1. MRC Mammalian Genetics Unit, Harwell, OX11 ORD, UK

    Steve D. M. Brown, Rachel E. Hardisty-Hughes & Philomena Mburu

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  1. Steve D. M. Brown
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  2. Rachel E. Hardisty-Hughes
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  3. Philomena Mburu
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Correspondence to Steve D. M. Brown.

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DATABASES

OMIM

otitis media

retinitis pigmentosa

Usher syndrome type I

Usher syndrome type II

Usher syndrome type III

FURTHER INFORMATION

European Conditional Mouse Mutagenesis Project (EUCOMM)

Knockout Mouse Project (KOMP)

North American Conditional Mouse Mutagenesis Project (NORCOMM)

The Encyclopedia of DNA Elements Project (ENCODE)

Glossary

Organ of Corti

The sensory neuroepithelia in the cochlea of the inner ear that contains the hair cells, it is the site of auditory transduction.

Stereocilia

Stereocilia are actin-filled hair-like projections on the surface of hair cells and are the mechanosensory organelles of hair cells. They share some similarities with microvilli and are organized into stereocilia bundles.

Cochlea

A coiled, snail-like structure that is the auditory organ of the inner ear. It contains the organ of Corti.

Pinna

The outer ear. Its purpose is to collect sound and funnel it down the ear canal to the tympanic membrane and middle ear.

Planar-cell polarity

Planar-cell polarity is the coordinated organization of groups of cells within the plane of the epithelium, manifested in the organ of Corti by the similar orientation of stereocilia bundle structures.

Contact righting test

A behavioural test in which mice are placed in a perspex tube, which is then inverted. The mice are examined for righting — the ability to correctly orient the body. Failure to right indicates a vestibular impairment.

Negative geotaxis test

A behavioural test in which mice are placed facing downwards on a steeply sloping grid. Failure to reverse and move up the grid indicates a vestibular impairment.

Click box test

A sensory test in which a click box, emitting a 20 kHz, 90 dB sound-pressure level tone burst, is held above the home cage to test for the Preyer reflex — the elicitation of startle response to auditory stimuli, manifested by a flick of the earlobe. Absence of the Preyer reflex indicates a hearing impairment.

Gene targeting

Molecular manipulation to delete a portion of a gene resulting in ablation of function (known as a knockout).

Gene trapping

A mutation strategy that uses insertion vectors to trap or isolate transcripts from flanking genes. The inserted sequence acts as a tag from which to clone the mutated gene.

Kinocilium

A single true cilium on the surface of hair cells that is involved with the growth and orientation of the stereocilia bundle.

Conductive deafness

Deafness that is caused by impairment of sound conduction through the outer or middle ears. Otitis media causes conductive deafness by impairing the transmission of sound through the middle ear.

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Brown, S., Hardisty-Hughes, R. & Mburu, P. Quiet as a mouse: dissecting the molecular and genetic basis of hearing. Nat Rev Genet 9, 277–290 (2008). https://doi.org/10.1038/nrg2309

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