The long-term goal of the proposed research is to understand the tissue interactions and molecular mechanism underlying induction, patterning and cell fate specification in the vertebrate middle ear. This study examines the tissue interactions and functional mechanisms involved in induction and morphogenesis of the vertebrate middle ear. The ear has multiple components that need to develop and interact correctly for normal hearing. Because the interactions are so complex, there are multiple ways that developmental defects occur through development. As a result of developmental (congenital) defects in a complex system such as the hearing apparatus, hearing loss is one of the most common birth defects (1 in 300-500 newborns affected), with about 10% conductive hearing loss. Middle and outer ear congenital and later anomalies resulting in conductive hearing loss include, microtia, atresia, cholesteatoma, exostoses, otoschlerosis, glomus tumor, myringosclerosis of the tympanic membrane, otitis media and trauma. The morphology of the chick middle ear was described nearly 30 years ago, but few studies of the tissue and molecular interactions required for initiation and patterning of the middle ear using modern molecular methods have been undertaken. Using the chicken embryo, with its numerous advantages as a model organism, crucial studies of both tissue interactions and signaling mechanisms can be accomplished. The chick offers a simple, accessible system in which a single bone, the columella develops, which is essential for sound transmission. Tissue interactions and signaling pathways from other complex mechanisms within the embryo, implicate gene candidates for a role in middle ear development. Signaling pathways have also been implicated by their expression patterns in the right place and at the right time. Gene expression in the chick can be altered by several means and has a high degree of spatial and temporal precision.
We aim 1) to determine the gene expression profile of the columella condensation, replacement and persistent cartilage, and timing of chondrogenesis and ossification of the columella using histology and in situ hybridization analysis, 2) determine if the pharyngeal endoderm, lying adjacent to the site of columella condensation is crucial for induction of the columella condensation by performing tissue manipulation and recombination experiments and 3) manipulate the Fgf and Wnt signaling pathways to determine their role in induction and later development of the columella. ? ? ?
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