Interactions between Notch signalling and SoxB transcription factors during the development and regeneration of sensory hair cells

The inner ear contains different sensory organs responsible for hearing and the perception of head movements. Each sensory organ contains a limited number of sensory cells, named hair cells. In mammals, the loss of auditory hair cells following a noise trauma, ototoxicity, or during aging is irreversible and causes permanent deafness. But in birds, fish and amphibians, inner ear hair cells are produced throughout life and regenerate following tissue injury. Our main objective is to identify the genes and signals involved in the production of hair cells during embryonic development and their post-traumatic regeneration in the chick inner ear. In the long term, our findings could contribute to the development of new therapies for deafness.

The overall objective of this project is to gain a better understanding of the mechanisms regulating the production of sensory hair cells in the inner ear. All sensory epithelia of the inner ear are composed of a regular mosaic of sensory hair cells separated from one another by non-sensory supporting cells. In mammals, the loss of auditory hair cells following an acoustic trauma, ototoxicity, or during aging is irreversible and is a major cause of deafness. On the other hand, hair cells can regenerate in birds and cold-blooded vertebrates. This is because in these species, the supporting cells can act as 'tissue stem cells' to generate on demand new hair cells throughout life. The signals and genetic networks controlling hair cell development and regeneration are just beginning to be elucidated. Among these are the Notch signalling pathway and the Sox2 transcription factor: both are required for the normal production of hair cells, and our preliminary data suggest that Notch regulates Sox2 expression in the developing chick inner ear. We will further investigate this question and the role of additional Sox genes during hair cell formation using gain-of-function and loss-of-function approaches. The experiments will be performed in two different contexts 1) during the embryonic production of hair cells, and 2) during the post-traumatic regeneration of hair cells, using the chick inner ear as a model system. Our findings will contribute to a better understanding of the genetic networks controlling sensory cell production and renewal in the ear, and could promote in the long term the development of new cures for human deafness. They could also have implications for other stem cell compartments where Notch signalling and Sox transcription factors are active.