MECHANISMS REGULATING COCHLEAR DEVELOPMENT

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): Dissecting function of FGF signal in cochlear formation Project Summary/Abstract I am interested in the mechanisms by which Fibroblast Growth Factors (FGFs) regulate cochlear formation. Fgf20 is expressed in the developing cochlea and deleting Fgf20 (Fgf20-/-) results in profound hearing loss in otherwise healthy mice. Examination of the inner ears of Fgf20-/- mice revealed that outer hair cells in the organ of Corti the sensory apparatus within the cochlea, were severely disrupted. Specifically, the cochlear sensory epithelium in Fgf20-/- mice contained large regions in which normal cellular differentiation failed to occur. It is likely that this loss of outer hair cells and disruption of ellular organization accounts for the profound hearing loss in these mice. Moreover, deletion of both Fgf9 and Fgf20 resulted in decreased cochlear size, which indicates that FGF9/20 might be important for sensory cell formation. The goal of my proposed research is to identify molecular and cellular functions of FGF9/20 during inner ear development. This knowledge is necessary for future studies that will test whether reactivation of FGF9/20 signaling in the adult inner ear can promote regeneration of the sensory epithelium. Expression patterns and the mutant phenotype demonstrate that FGF9/20 are critical and essential regulators of cochlear development. To consider FGF9/20-based therapies for sensory regeneration, it is essential to understand the normal regulation and function of FGF9/20 during inner ear sensory development. In this proposal, I will identify cellular targets (epithelium vs. mesenchyme) by which FGF20 (and FGF9) can regulate different stages of cochlear development and sensory epithelial patterning and use Next Gen mRNA sequencing to identify downstream targets of FGF9/20 in the developing inner ear. Understanding the mechanisms by which FGF9/20 regulates cochlear development and patterning will be essential to develop methods to therapeutically activate FGF9/20-regulated developmental programs in the adult to promote the repair of damaged sensory tissue.