Roles of fibroblast growth factors in inner ear development

Understanding the molecular and genetic mechanisms responsible for the development of the vertebrate inner ear, which mediates hearing and equilibrium, is an ongoing quest in developmental biology. Most of the cells found in the sensory tissue of the mature inner ear are derived from an ectodermal placode that is located adjacent to the developing hindbrain. This tissue undergoes complex morphogenesis to form auditory and vestibular compartments which have distinct morphologic characteristics along each of the developmental axes. Otic development involves signaling interactions within and between otic and non-otic tissues. However, the molecular basis of otic morphogenesis and axis formation remains relatively unexplored. This study uses the mouse model to assess the role of the Fibroblast Growth Factor (FGF) signaling system in otic development. The work described herein analyses expression patterns of the members of Fg/'gene family and examines specific roles of Fgf3 and Fgfl6 in inner ear morphogenesis. We show that Fgf'16 is one of the earliest regionally restricted transcripts expressed in otic tissue and is polarized along the antero-posterior otic axis. Simultaneous knock out of Fgfl6 function and expression of Cre recombinase in its place allowed us to determine the consequences of inactivating Fgfl6 and to examine the fate of mouse posterior otic cells. We show that Fgfl6 does not have a unique role in inner ear development and describe the fates of Fgf'16 expressing otic cells in anterior and posterior semicircular canals, the three ampullary cristae, and the cochlear stria vascularis. In addition, this thesis shows that Fgf3 is required for dorsal pattering and morphogenesis of the inner ear epithelium. The range of malformations observed in Fgf3 mutants has close parallels with those seen in hearing impaired patients. Through a series of conditional mutagenesis experiments, we also suggest that there is an early placode stage requirement for hindbrain-expressed Fgf3 to induce proper development of the endolymphatic duct. Taken together, this study provides new information on the normal development of the inner ear and the factors that regulate the process of otic morphogenesis, providing insights into genetic mechanisms responsible for the myriad of human inner ear malformations.