The goal of our research is to understand the timing and molecular mechanisms that control patterning and cell fate specification in the developing inner ear. The inner ear, unique to vertebrates, is remarkable for the complex three-dimensional arrangement of its constituent cells, which include neurons, sensory receptors and non-sensory cells organized into tubules, ducts and other specialized tissues. It is likely that the morph genetic mechanisms required to form such structures will be shared by vertebrates. In humans and animal models, disruption of the precise morphology of the inner ear due to congenital anomalies or disease can result in deafness and/or to difficulties with balance and equilibrium. Our efforts to understand the fundamental defects that result in inner ear abnormalities are focused on both the normal processes of development and on the cascade of events that can arise as a result of a specific genetic defect. In this study, we aim to: (1) undertake lineage analysis of the progenitor cells in the ready chicken otocyst to reveal when distinct cell lineages diverge, such as sensory vs. non-sensory or neurogenic vs. nonneurogenic; (2) undertake lineage analysis in the mouse inner ear to determine whether hair cells and supporting cells share a common progenitor and whether there are cell lineage (compartment) boundaries in the organ of Corti; and (3) explore the role of the Wnt signaling pathway in cell fate specification in the ear, particularly with respect to the auditory vs. vestibular cell fate decision. Our studies will employ replication defective retroviral vectors to limit gene transfer to a small number of otic cells and their progeny. To study the Wnts, we will use replication-competent viruses to generate widespread misimpression for both gain-offunction and loss-of-function experiments. Together, the proposed studies should provide insight on the divergence of inner ear lineages. Our studies are designed to test a model of inner ear patterning that is based on the establishment of compartments and boundaries within the otic epithelium. Our data to date reveal that the auditory-vestibular fate decision can be manipulated through Wnt/b-catenin signaling. These findings, and new data generated from this study, may provide baseline data for a therapeutic strategy to direct stem cells along different developmental fates according to which sensory organ cell types may need to be replaced.
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