Karen P. Steel

The recessive mouse mutant whirler (wi) shows no response to sound and exhibits circling and head‐tossing behaviour, indicative of both auditory and vestibular dysfunction. The wi mutation maps genetically to mouse chromosome 4. We examined the organ of Corti of whirler mutants to explore the possibility that the wi mutation affects sensory hair cells. Scanning electron microscopy (SEM) reveals that the specialised microvilli (stereocilia) that are projected by the sensory hair cells and are vital for sound transduction are abnormal in wi homozygotes. Specifically, wi homozygous inner hair cell (IHC) stereocilia are approximately half the length of equivalent stereocilia in heterozygous littermates. They are arranged normally into ranks, but the gradation in height and width of stereocilia in adjacent ranks is less prominent in wi homozygotes. Analysis of IHC stereocilia during the course of their development shows that, by embryonic day 18.5, mutant stereocilia are already significantly shorter than those in controls. Mutant stereocilia elongate at a normal rate, at least until postnatal day 1, but prematurely stop elongating between postnatal days 1 and 4. Stereocilia length then decreases. At postnatal day 15, outer hair cell (OHC) stereocilia in wi homozygotes appear short and are arranged in a rounded, “U” shape rather than the normal “W” or “V” shape. Eventually, both IHCs and OHCs degenerate. We show that the whirler locus encodes a protein(s) required for the elongation and maintenance of IHC and OHC stereocilia. J. Comp. Neurol. 450:94–102, 2002.

Within the mammalian inner ear there are six separate sensory regions that subserve the functions of hearing and balance, although how these sensory regions become specified remains unknown. Each sensory region is populated by two cell types, the mechanosensory hair cell and the supporting cell, which are arranged in a mosaic in which each hair cell is surrounded by supporting cells. The proposed mechanism for creating the sensory mosaic is lateral inhibition mediated by the Notch signaling pathway. However, one of the Notch ligands, Jagged1 ( Jag1 ), does not show an expression pattern wholly consistent with a role in lateral inhibition, as it marks the sensory patches from very early in their development—presumably long before cells make their final fate decisions. It has been proposed that Jag1 has a role in specifying sensory versus nonsensory epithelium within the ear [Adam, J., Myat, A., Roux, I. L., Eddison, M., Henrique, D., Ish-Horowicz, D. & Lewis, J. (1998) Development (Cambridge, U.K.) 125, 4645–4654]. Here we provide experimental evidence that Notch signaling may be involved in specifying sensory regions by showing that a dominant mouse mutant headturner ( Htu ) contains a missense mutation in the Jag1 gene and displays missing posterior and sometimes anterior ampullae, structures that house the sensory cristae. Htu /+ mutants also demonstrate a significant reduction in the numbers of outer hair cells in the organ of Corti. Because lateral inhibition mediated by Notch predicts that disruptions in this pathway would lead to an increase in hair cells, we believe these data indicate an earlier role for Notch within the inner ear.

Little is known of the molecular basis of normal auditory function. In contrast to the visual or olfactory senses, in which reasonable amounts of sensory tissue can be gathered, the auditory system has proven difficult to access through biochemical routes, mainly because such small amounts of tissue are available for analysis. Key molecules, such as the transduction channel, may be present in only a few tens of copies per sensory hair cell, compounding the difficulty. Moreover, fundamental differences in the mechanism of stimulation and, most importantly, the speed of response of audition compared with other senses means that we have no well-understood models to provide good candidate molecules for investigation. For these reasons, a genetic approach is useful for identifying the key components of auditory transduction, as it makes no assumptions about the nature or expression level of molecules essential for hearing. We review here some of the major advances in our understanding of auditory function resulting from the recent rapid progress in identification of genes involved in deafness.

Methods The views expressed in this article have been developed over many years and are based on my personal experience of research in the subject, discussions with scientists and clinicians as well as with people affected by deafness, and extensive reading of the literature, only a tiny proportion of which has been cited here.

Hearing impairment is a common human condition, but we know little about the molecular basis of cochlear function. Shaker-with-syndactylism (sy)isaclassic deaf mouse mutant and we show here that a second allele, sy^ns, is associated with abnormal production of endolymph, the fluid bathing sensory hair cells. Using a positional candidate approach, we demonstrate that mutations in the gene encoding the basolateral Na-K-Cl co-transporter Slc12a2(Nkcc1, mBSC2) cause the deafness observed in sy and sy^ns mice. This finding provides the molecular basis of another link in the chain of K⁺ recycling in the cochlea, a process essential for normal cochlear function.

Hereditary deafness can be the result of defects in any one of a large number of genes. Two more of these have now been identified, in Nature Genetics and in this issue of Science (see Probst et al. and Wang et al.), as coding for a protein called a-tectorin and an unconventional myosin. In their commentary, Steel and Brown explain how the identification of these and other genes underlying deafness allows a proposal to be put forward for their role in hearing.

Defects in different genes underlie the many kinds of genetic deafness. In this issue, [ Vahava et al .][1] report that a mutation in the transcription factor POU4F3 is the cause of deafness in a large Israeli family. In her commentary, Steel discusses how the malfunctioning of this transcription factor may lead to progressive deafness, with onset at age 18. [1]: http://www.sciencemag.org/cgi/content/short/279/5358/1950