Final Report Summary - HAIRBUNDLE (Assembling the puzzle of the operating auditory hair bundle)
Hearing has dazzling characteristics: the ability to detect acoustic energy close to the thermal noise, to cope with sound-pressure levels covering 6 orders of magnitude, from 20 mPa to 20 Pa (0 to 120 decibels, 12 orders of magnitude in acoustic power), and to discriminate a 0.3% variation in sound frequency. Hearing also derives its unique status among the senses from the unparalleled human ability to make sense out of sounds, through the development of spoken language and music, another sound-based communication system.
Most of hearing properties stem from the processing of sound waves by the sensory cells, called hair cells, of the hearing organ, the cochlea. In a vast majority of cases, hair cell failure originates in the hair bundles, the apical compartment of hair cells, understandably since they operate
mechano-electrical transduction (MET) of sound. This deceptively simple term hides a complex
assembly organized in the hair bundle and likely contributing to important mechanical properties, to the way transduction channels are opened by forces generated by sound waves, and functionally, to stages of sound amplification and tuning, as well as distortion and suppressive masking. This is why the main focus of this project is set on how the hair bundle machinery is assembled.
The present project aims at building a more integrated view of the way the hair bundle works,
concentrating on three particular aspects:
I) how components of the basal MET machinery are assembled?
II) the coupling between MET and stereocilia F-actin polymerization
III) the interplay between MET, waveform distortions, and masking
In the framework of this project, major achievements include:
(1) the characterization of several mouse models of deafness that shed new light on the molecular machinery that allows inner ear hair cells to detect a sound wave and convert it into an electric signal. The precise role(s) of Protocadherin-15 isoforms, Cadherin-23, Harmonin, Sans, Myosin VIIa, Nherf1, Nherf2, Myosin IIIa, Myosin IIIb, Myosin 1c, Formin-1, Spire-1, Clarin-1, Otogelin and Otogelin-like have been elucidated.
(2) the successful rescue of the hearing and vestibular functions of an Usher syndrome mouse models by gene therapy, which represents an important milestone towards the development of therapeutic options for hearing deficiencies in a field with yet unmet medical needs.
(3) the demonstration of a role for two Usher proteins in the maturation of a class of interneurons essential to the development of the auditory cortex, which unraveled the so far unsuspected role of the central nervous system in the physiopathology of Usher syndrome.
Regarding the outcomes:
(1) The establishment of the key role of several hair bundle proteins foster additional experimental approaches and concepts regarding the morphogenesis, maturation, and maintenance of the hair bundle.
(2)Studies of isolated and syndromic (Usher syndrome, 1st cause of deaf-blindness) hearing loss enabled us to set up reliable, early, efficient diagnostic tests: The hearing (113 confirmed and candidate genes included in our “Hear Panel”) and the Usher syndrome (11 Usher genes) genotyping panels. These data are essential and determinant for genetic counseling, educational orientation, the use of prostheses and the introduction of new treatments.
(3)Identification of new source of off-frequency hearing helps guide potential transfer of Masking tuning recordings into clinics to depict origin of the difficulties some patients experience in noisy environments, namely a hypervulnerability to low-frequency sounds.
Most of hearing properties stem from the processing of sound waves by the sensory cells, called hair cells, of the hearing organ, the cochlea. In a vast majority of cases, hair cell failure originates in the hair bundles, the apical compartment of hair cells, understandably since they operate
mechano-electrical transduction (MET) of sound. This deceptively simple term hides a complex
assembly organized in the hair bundle and likely contributing to important mechanical properties, to the way transduction channels are opened by forces generated by sound waves, and functionally, to stages of sound amplification and tuning, as well as distortion and suppressive masking. This is why the main focus of this project is set on how the hair bundle machinery is assembled.
The present project aims at building a more integrated view of the way the hair bundle works,
concentrating on three particular aspects:
I) how components of the basal MET machinery are assembled?
II) the coupling between MET and stereocilia F-actin polymerization
III) the interplay between MET, waveform distortions, and masking
In the framework of this project, major achievements include:
(1) the characterization of several mouse models of deafness that shed new light on the molecular machinery that allows inner ear hair cells to detect a sound wave and convert it into an electric signal. The precise role(s) of Protocadherin-15 isoforms, Cadherin-23, Harmonin, Sans, Myosin VIIa, Nherf1, Nherf2, Myosin IIIa, Myosin IIIb, Myosin 1c, Formin-1, Spire-1, Clarin-1, Otogelin and Otogelin-like have been elucidated.
(2) the successful rescue of the hearing and vestibular functions of an Usher syndrome mouse models by gene therapy, which represents an important milestone towards the development of therapeutic options for hearing deficiencies in a field with yet unmet medical needs.
(3) the demonstration of a role for two Usher proteins in the maturation of a class of interneurons essential to the development of the auditory cortex, which unraveled the so far unsuspected role of the central nervous system in the physiopathology of Usher syndrome.
Regarding the outcomes:
(1) The establishment of the key role of several hair bundle proteins foster additional experimental approaches and concepts regarding the morphogenesis, maturation, and maintenance of the hair bundle.
(2)Studies of isolated and syndromic (Usher syndrome, 1st cause of deaf-blindness) hearing loss enabled us to set up reliable, early, efficient diagnostic tests: The hearing (113 confirmed and candidate genes included in our “Hear Panel”) and the Usher syndrome (11 Usher genes) genotyping panels. These data are essential and determinant for genetic counseling, educational orientation, the use of prostheses and the introduction of new treatments.
(3)Identification of new source of off-frequency hearing helps guide potential transfer of Masking tuning recordings into clinics to depict origin of the difficulties some patients experience in noisy environments, namely a hypervulnerability to low-frequency sounds.