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


  HEADChristine PETIT / cpetit@pasteur.fr
  MEMBERSAshmore Jonathan , El-Amraoui Aziz, El-Bahloul Amel, Hardelin Jean-Pierre, Leibovici Michel, Levilliers Jacqueline, Safieddine Saaid, Verpy Elisabeth, Weil Dominique
Boutet de Monvel Jacques,Caberlotto Elisa,Delmaghani Sedigheh,Etournay Raphaël,Foucher Isabelle ,Hering Julien, Kamiya Kazusaku,Legendre Kirian ,Lepelletier Léa,Michalski Nicolas
Alegria-Prevot Olinda ,Bizard Emilie ,Chardenoux Sébastien,Gillet Dominique,Michel Vincent ,Nouaille Sylvie,,Perfettini Isabelle,Poisson Carine


  Annual Report

Our research projects have two tightly linked goals: (i) to elucidate the cellular and molecular mechanisms that underlie the development of the auditory system and the way it processes of the sensory information, and (ii) to identify the causative genes for human hearing impairment as a means of elucidating the pathogenesis of the corresponding forms of deafness. To date our work has focused mainly on the sensory organ, the cochlea and the hereditary early-onset forms of hearing impairment. We recently extended our focus of interest to the first and second (brain stem nuclei) order neurons and to the genetic basis of presbycusis, the very frequent age-related sensorineural hearing loss.

Progress in 2007 included the following:

1. The endocochlear potential (EP). EP produced by the stria vascularis of the cochlea, provides more than half of the current driving force for transduction in auditory hair cells. By studying deaf mice defective in the gap junction protein connexin 30 that, we showed, fail to develop EP, we have uncovered a novel pathogenic process for deafness. It consists in the instrastrial fluid-blood barrier disruption of the capillaries supplying the stria vascularis compartment. This anomaly, by creating an electrical shunt into the stria vascularis, could readily explain the absence of the EP in these mice.

2. The molecular physiology of sensory hair cell synapses. By membrane capacitance and ionic current measurements, we have provided evidence showing that one of the two categories of auditory sensory cells, the outer hair cell, does display synaptic exocytosis at its early developmental stage, albeit with an as yet unknown role. By studying otoferlin-null mice, we could show thatotoferlin (DFNB9 deafness gene product), in addition to its predicted role as the major Ca2+sensor of the mature inner hair cell synapse, the genuine sensory cells, is also required for exocytosis at the outer hair cell transient ribbon synapse.

3. The structure/function of links of the hair bundle, the mechano-electrical transduction organelle. Within the hair bundle, the stereocilia are connected by the tip link, supposed to be tethered by the mechanotransduction channel and various subsets of lateral links of unknown function. We have unravelled the molecular composition of the ankle links, the basal lateral links of the growing stereocilia. They are composed of the proteins encoded by three genes defective in Usher syndrome type II (sensorineural deafness associated to blindness), usherin, Vlgr1, whirlin. By recording mechanotransduction currents in mutant mice lacking the ankle links, we have uncovered that these links are essential for the functional polarity of the hair bundle.

4. The cell-cell junctions of the sensory hair cells. These junctions have a specific structure and support tension forces generated by sound stimulation. We have studied the dynamics of shroom2, a submembranous tight junctions protein which is a novel myosin VIIa ligand that also binds to ZO-1 and F-actin. We observed that this protein is especially abundant at the junctions of outer hair cells with their supporting cells, that are under mechanical stress during sound stimulation as a result of voltage-dependent generated axial forces (electromotility).

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

Gpa.jpg

Mechanoelectrical transduction current as a function of the displacement of the hair bundle. In the absence of the ankle links (Vlgr1-/- mice), the mechanoelectrical channels open upon deflection in the negative direction.



  Publications

Cohen-Salmon M, Regnault B, Cayet N, Caille D, Demuth K, Hardelin J-P, Janel N, Meda P & Petit C (2007) Connexin30 deficiency causes intrastrial fluid-blood barrier disruption within the cochlear stria vascularis. Proc Natl Acad Sci USA 104, 6229-6234.

Michalski N, Michel V, Bahloul A, Lefèvre G, Barral J, Yagi H, Chardenoux S, Weil D, Martin P, Hardelin J-P, Sato M & Petit C (2007) Molecular characterization of the ankle link complex in cochlear hair cells and its role in the hair bundle functioning. J Neurosci 27, 6478-6488.

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 newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat Genet 38, 770-8.

Dodé C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler M-L, Lespinasse J, Lienhardt-Roussie A, Mathieu M, Moerman A, Morgan G, Murat A, Toublanc J-E, Wolczynski S, Delpech M, Petit C, Young J & Hardelin J-P (2006) Kallmann syndrome: mutations in the genes enco ding prokineticin-2 and prokineticin receptor-2. PLOS Genet 2, 1648-1652.

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, 277-89.





Activity Reports 2007 - Institut Pasteur
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