A COMPARATIVE STUDY OF FGFR3 SIGNALING DURING THE DEVELOPMENT OF THE ORGAN OF CORTI AND BASILAR PAPILLA
Jacques, Bonnie E
Jeffery, William R
Kelley, Matthew W
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Most age-related hearing loss is the result of the accumulated death of inner ear hair cells over a life span. Human hair cells lack the ability to be regenerated once they die and thus there is a need to understand the processes which regulate hair cell formation. Unlike the mammalian ear, the avian cochlea has the ability to regenerate lost hair cells and thus there exists an ongoing race to find the key to regeneration in the mammalian ear. Human hearing is dependent on the interactions between numerous cell types yet very little is known about the pathways which regulate the development of the functionally essential support cells of the mammalian cochlear sensory epithelium. This study aims to elucidate some of the genetic pathways involved in hair cell and support cell differentiation in the developing cochlea. Specifically, the role of Fgfr3 signaling in pillar cell and hair cell differentiation will be revealed through the use of an in vivo mutant mouse model containing a null Fgf8 gene and in vitro whole organ culturing of the embryonic cochlear sensory epithelia of mice and chickens. The classic localize, activate, inhibit scheme will be employed. This study will demonstrate that Fgf8 and Fgfr3 are expressed by inner hair cells and pillar cells, respectively, and are required throughout development for normal differentiation and pattern formation of the organ of Corti. Inhibition of the receptor or ligand results in the loss of pillar cells and ectopic formation of hair cells, while activation of this pathway inhibits hair cell formation and induces pillar cells or activation of these genes and their proteins have on the formation of hair cell and support cell types. This study also takes a comparative approach by addressing the similarities and differences of the Fgfr3 signaling pathway in the mammalian organ of Corti and the avian basilar papilla. Fgfr inhibition in the developing basilar papilla causes an increase in hair cell density via the direct transdifferentiation of support cells into hair cells suggesting a role for this signaling pathway in the ability to regenerate hair cells.