Auditory transduction : from physiology to deciphering a molecular machinery

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The lecture focused on the very first stage of auditory perception, auditory mechano-electrical transduction (or MET) (the subject of a previous lecture (2002-2003)). The introduction briefly recalled how our understanding of the biophysical principles of auditory transduction was built up, from the pioneering work of physicists and physiologists in the late 19th^century, establishing the principles of cochlear tonotopy, to the 1960-1990 period, during which two other major aspects of auditory transduction were brought to light: on the one hand, the existence of an active process amplifying the vibrations of the sensory epithelium in response to sound, visionarily postulated by Thomas Gold in 1948, and responsible for the ear's extreme sensitivity ; and, secondly, the identification of the mechanoreceptive antenna of hair cells as the ciliary tuft, a polarized structure formed of stereocilia in whose membrane the mechanoelectrical transduction (MET) channels are located, and the development of the gating spring model which elegantly accounts for the properties of this transduction.

In the second part of the lecture, we retraced the steps that led to the success of the genetic approach to molecular deciphering of cochlear physiology, which our laboratory embarked on in the early 1990s. These steps included the identification of the first loci responsible for profound deafness in children, followed by the development of complementary cochlear DNA libraries derived from subtractive hybridization, leading to the isolation of candidate genes, and finally the discovery of the genes themselves. Today, over a hundred genes responsible for non-syndromic (isolated) hearing loss are known, and it is estimated that they account for around three-quarters of cases of hereditary, early-onset and profound sensorineural hearing loss. In addition, some 300 genes are responsible for syndromic deafness. Estimates made in mice, based on the proportion of inactivated genes that lead to hearing impairment, predict that around 200 genes responsible for rare and mostly syndromic forms of deafness have yet to be identified in humans.

In the third part, we addressed the cellular and molecular mechanisms of the pathophysiology of hereditary hearing impairment, initiated in the mid-1990s by our group and others, through the multidisciplinary study of mouse models of human hereditary deafness. We have focused on proteins identified in the context of Usher syndrome, the most common inherited disorder affecting both hearing and vision. The proteins encoded by the six genes involved in the most severe form of Usher syndrome, known as type 1 (or USH1) (namely protocadherin 15, cadherin 23, harmonin, myosin VIIa, sans, and CIB2), and at least a partial elucidation of their key roles in the MCT machinery were presented. Protocadherin 15 and cadherin 23, now renamed " cadherinrelated 15 " and " cadherin-related 23" (cdhr15 and cdhr23), are the two Ca2+-dependent transmembrane adhesion proteins that form the tip-link. Recent work by Marco Sotomayor and David Corey suggesting, on the basis of crystallographic data and molecular dynamics simulations, a "handshake" interaction mechanism of the N-termini of the two cadherins, very different from known interactions between classical cadherins, and capable of sustaining tensile forces of the order of 400 pN, was discussed. The diversity of interactions between classical cadherins and between protocadherins was discussed in some detail, as these provide an informative context for considering interactions between cdhr15 and cdhr23, pending more definitive experimental data. The other proteins encoded by Usher 1 genes form a molecular complex that anchors the apical part of the tip-link to the actin filaments of the stereocilia. These proteins encoded by Usher 1 genes thus form the core of the MCT machinery; they are also essential for ciliary tuft morphogenesis.