Genetics and Physiology of Hearing - INSERM (UMRS 587) – UPMC Paris-6 - Collège de France  

  HEADChristine PETIT /
  MEMBERSPr Petit Christine, Pr Ashmore Jonathan, Dr El-Amraoui Aziz, Dr El-Bahloul Amel, Dr Hardelin Jean-Pierre, Dr Leibovici Michel, Dr Levilliers Jacqueline, Dr Safieddine Saaid, Dr Verpy Elisabeth, Dr Weil Dominique Dr Boutet de Monvel Jacques, Caberlotto Elisa, Dr Delmaghani Sedigheh, Dr Étournay Raphaël, Dr Foucher Isabelle, Dr Hering Julien, Legendre Kirian, Lepelletier Léa, Dr Michalski Nicolas Dr Alegria-Prévot Olinda, Bizard Emilie, Chardenoux Sébastien, Michel Vincent, Nouaille Sylvie, Perfettini Isabelle, Poisson Carine Gillet Dominique

  Annual Report

Our research projects have two tightly linked goals: (i) to decipher the cellular and molecular mechanisms that underlie the development of the auditory system and the way it processes acoustic signals, and (ii) to identify the genes causative for deafness in humans, early and late onset forms as well as forms including retinal defects, and to elucidate the corresponding pathogenesis in a therapeutic perspective.

Progress in 2008 included:

- the first in vivodemonstration of the essential role of the kinocilium in the establishment of the cochlear hair bundle planar polarity by using conditional knockout (collaboration with Ping Chen, Emory University, Atlanta). The hair bundle, the mechanoreceptive structure of the cochlear sensory hair cells, is composed of actin-filled processes, the stereocilia and an authentic cilium, the kinocilium that disappears at mature stage;

- the deciphering of the molecular composition of the cortical lattice of the outer hair cells (OHCs), one class of cochlear hair cells. This lattice is involved in their electromotile property that underlies their role in cochlear amplification;

- the finding that synaptic exocytosis in the OHCs, although only transiently present, requires, as in the inner hair cells (IHCs), the genuine sensory cells, otoferlin, a transmembrane C2-domain protein,

- the finding that the sensorineural deafness associated to severe immunodeficiency that result from adenylate kinase-2 (AK2) failure is accounted by the presence of this enzyme at the vessel walls of the cochlear stria vascularis (collaboration with Marina Cavazzana-Calvo and Alain Fischer, Necker, Paris).

Moreover, two major insights into the functions of the links of the hair bundle have been obtained. One enlightens the role of the earliest hair bundle lateral links and the other, the role of the only hair bundle lateral links persisting in mature OHCs, the horizontal top connectors.

1. Implication of fibrous links of the immature hair bundle in its cohesion, orientation and the differential growth of its stereocilia: advances in the pathogenesis of Usher syndrome type I hearing impairment.

The planar polarity and staircase-like pattern of the stereocilia within the hair bundle are essential to the mechanoelectrical transduction function of inner ear sensory cells. Mutations in genes encoding myosin VIIa, harmonin, cadherin-23, protocadherin-15 or sans cause Usher syndrome type I (USH1), characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa leading to blindness. In the corresponding mouse models, the hair bundle is disorganized. We have shown that mouse models for the five USH1 genetic forms share hair bundle morphological defects. Hair bundle fragmentation and misorientation (25-50° mean kinociliary deviation, depending on the mutant) were detected as early as embryonic day 17, i.e. as soon as the hair bundle emerges. In addition, abnormal differential elongation of stereocilia rows occurred in the first postnatal days. In the emerging hair bundles, myosin VIIa, the actin-binding submembrane protein harmonin-b, and the interstereocilia-kinocilium lateral link components cadherin-23 and protocadherin-15, are all concentrated at stereocilia tips, in accordance with their known in vitro interactions. Soon after birth, harmonin-b switched from the tip of the stereocilia to the upper end of the tip link, which also comprises cadherin-23 and protocadherin-15. This positional change did not occur in mice deficient for cadherin-23 or protocadherin-15. From these results, tension forces applied to the early hair bundle lateral links (interstereocilia and kinociliary links) and to the tip link, both of which are composed of cadherin-23 and protocadherin-15, and that can be anchored to actin filaments via harmonin-b, were concluded to play a key role in hair bundle cohesion and proper orientation for the former, and in stereociliary elongation for the latter. The origin of the tension forces applied to the early developing hair bundles is the next issue to be solved.

2. Deciphering of the origin of acoustic distortions: the role of the horizontal top connectors.

Although the cochlea is an amplifier and a remarkably sensitive and finely tuned detector of sounds, it also produces conspicuous mechanical and electrical distortions of sound waveforms. These distortions reflect nonlinear mechanical interactions within the cochlea. By allowing one tone to suppress another (masking effect), they contribute to speech intelligibility. Tones can also combine to produce sounds with frequencies not present in the acoustic stimulus. These sounds compose the otoacoustic emissions that are extensively used to screen hearing in newborns. A genetic approach led us to identify the unsuspected roles of the horizontal top connectors of the hair bundle of the outer hair cells (OHCs) in the masking effect and cochlear waveform distortions. Stereocilin, a protein defective in a recessive form of human deafness, was detected in association with horizontal top connectors (Figure 1). These links were absent in stereocilin-null mutant mice, which became progressively deaf. At the onset of hearing, however, their cochlear sensitivity and frequency tuning were almost normal, although masking was much reduced and both acoustic and electrical waveform distortions were completely lacking (Figure 2). From this unique physiological situation, we could ascribe a prominent role to non-linear hair bundle stiffness related to the top connectors in waveform distortions.

Keywords: Audition, Deafness, Usher syndrome, Sensorineural deficits, Sensorineural physiology, Human genetics, Cell biology, Electrophysiology, Biophysics, Biochemistry


Figure 1. OHC hair-bundle morphology in P14 wild-type (Strc+/+) and stereocilin null (Strc-/-) mice.

Detailed views of single OHC hair bundles. Top connectors (arrows in left image) are not detected in the Strc-/-mouse, whereas tip links (arrowheads in right image) are present. Scale bars: 0.25 µm.


Lefèvre G, Michel V, Weil D, Lepelletier L, Bizard E, Wolfrum U, Hardelin J-P & Petit C (2008) A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth. Development 135, 1427-1437.

Legendre K, Safieddine S, Küssel-Andermann P, Petit C, El-Amraoui A. (2008) αII/βV spectrin bridges the plasma membrane and cortical lattice in the lateral wall of the auditory outer hair cells. J Cell Sci, 121, 3347-56.

Verpy E, Weil D, Leibovici M, Goodyear RJ, Hamard G, Houdon C, Hardelin J-P, Richardson GP, Avan P & Petit C (2008) Stereocilin-deficient mice reveal the origin of cochlear waveform distortions Nature , 456, 255-8.

Delmaghani S, del Castillo FJ, Michel V, Leibovici M, Aghaie A, Ron U, Van Laer L, Ben-Tal N, Van Camp G, Weil D, Langa F, Lathrop M, Avan P & Petit C (2006) Mutations in the gene encoding pejvakin, a novel protein expressed in the afferent auditory pathway, cause DFNB59 auditory neuropathy in man and mouse. Nature Genet 38, 770-778.

Roux I, Safieddine S, Nouvian R, Grati M, Simmler M-C, Bahloul A, Perfettini I, Le Gall M, Rostaing P, Hamard G, Triller A, Avan P, Moser T & Petit C (2006) Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse. Cell 127, 277-289.

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