The early development of the inner ear occurs in three phases: formation of the otic placode, the earliest rudiment of the inner ear; morphogenesis of the otic placode, forming the otic pit (cup) and otocyst; and axis formation and regional patterning of the otocyst. Each phase is characterized by inductive interactions among different tissues. Although several signaling systems have been implicated in the control of these phases, Fibroblast Growth Factor (FGF) signaling clearly plays a critical role and is the focus of this proposal. This project combines the broad technical and scientific expertise of two investigators and uses two animal models to examine the cellular, molecular and genetic control of early inner ear development. To study the formation and patterning of the rudiments of the inner ear we will conduct experiments designed to achieve three specific aims. First, using tissue recombination experiments and modern molecular techniques, we will establish how fgf19, Wnt8c and fgf3, critical factors that we identified in the previous project period in formation of the otic placode, are localized in the cephalic paraxial mesoderm of the early chick embryo. This will allow us to determine how the rudiments of the inner ear are positioned within the head of the developing embryo. Second, we will determine the roles of Fgf4 and Fgf8 in formation of the rudiments of the inner ear. Expression studies, experimental embryology and genetic analyses from the previous project period strongly implicated these two factors in inner ear development. Third, we will determine and compare the roles of Fgf16 and Fgf3 in the patteming of the rudiments of the inner ear in mouse and chick. Expression studies and analyses of Fgf3/Fgf10 mutant embryos from the previous project period led to the hypothesis that these two factors play essential roles in formation of the otic axes and/or specification of cell types within the developing inner ear. This hypothesis will be rigorously tested taking advantage of the unique strengths of the two animal model systems that we employ in our studies. By achieving these three aims, we will gain important new information on the normal development of the inner ear and the FGFs that regulate its formation and patterning. Additionally, our studies will furnish insight into mechanisms by which these developmental processes go awry, underlying the formation of serious birth defects of the auditory system in humans.
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