DEVINAC · Identifying the proteins of the cochlear mechanoelectrical transduction machinery that are also involved in the development of auditory cortex interneurons.

Identifying the proteins of the cochlear mechanoelectrical transduction machinery that are also involved in the development of auditory cortex interneurons.

Hearing loss is a major concern and serious burden for Public Health as it is affecting 466 million worldwide according to the World Health Organization. Genetic research into hereditary forms of deafness in humans has largely contributed to the deciphering of the molecular physiology of the auditory sensory organ, the cochlea. Since the discovery of the first gene responsible for deafness in both humans and mice, the Usher syndrome gene encoding myosin-VIIa, about 110 genes responsible for non-syndromic forms of deafness and about 300 genes responsible for syndromic forms have been reported in humans and/or mice. By contrast, the genetic approach has provided little information about the central auditory system. One possible explanation for this discrepancy is that intrinsic auditory central dysfunction may be concealed by peripheral deficits in some genetic forms of deafness. Indeed, my hosting team recently discovered that the Usher syndrome genes encoding protocadherin-15 (cdhr15) and cadherin 23 (cdhr23), the cadherin-related proteins forming the tip links are also expressed by precursors of a subpopulation of GABAergic inhibitory parvalbumin interneurons in the auditory cortex. The extent to which central deficits are masked by peripheral ones in genetic forms of deafness is currently unknown. This evaluation is of particular importance because early prosthetic intervention is based on the revival of auditory cortex microcircuits, setting new challenges for clinical practice and the development of adapted auditory rehabilitation methods. The team I integrated is interested in addressing possible central auditory deficits in genetic forms of deafness. Our previous results demonstrating the coexistence of intrinsic central auditory deficits with peripheral deficits point to the importance of extending this study to other molecules. To date, eight other proteins make up the mechanoelectrical transduction molecular machinery in the hair bundle: through their interaction with cdhr23 and cdhr15, they form the upper and the lower tip-link complex, respectively. Therefore, the possibility that the entire Usher syndrome 1 complex and other molecular components of the mechanoelectrical transduction machinery are involved in the development of cdhr15/cdhr23-expressing auditory cortex interneuron precursors is an attractive working hypothesis. Taking this into account, my project was divided in two main aims: Aim 1) To determine which proteins of the mechanoelectrical transduction machinery, in addition to cdhr15 and cdhr23, are involved in the development of cortical interneurons. Aim 2) To determine whether cdhr15 and cdhr23 are essential for the migration of interneuron precursors to the cortex and for their integration within auditory cortex microcircuits.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз