The goal of this research is to understand the molecular mechanisms that control patterning and cell fate determination 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 morphogenetic 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 anomalities or disease can result in deafness, and/or difficulties with balance and equilibrium, often accompanied by profound vertigo and nausea. The PI's 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 gene defect.
The aims are to: (1) undertake a lineage analysis of the progenitor cells in the early chick otocyst to reveal when distinct cell lineages diverge, such as neurogenic vs. non-neurogenic or sensory vs. non-sensory; (2) undertake a lineage analysis of the mouse organ of Corti to determine whether hair cells and supporting cells share a common progenitor; (3) generate a fate map the chick otic cup to understand the relationships between gene expression and morphogenetic movements; and (4) force both focal and global perturbations of gene expression domains to help define the rules governing pattern formation in the eveloping inner ear. The studies will employ focal dye injections as well as infection with pseudotyped replication-defective retroviral vectors to limit gene transfer to a small number of otic cells and their progeny.
The fourth aim will use replication-competent viruses to generate widespread misexpression of patterning genes. Together, the proposed studies should provide insight on the divergence of inner ear lineages and what role, if any, morphogenic movements and patterning genes play in the process. Their studies are designed to test a model of inner ear patterning that is based on the establishment of compartments and boundaries. The information provided by these animal studies may aid in understanding the molecular-genetic basis of human birth defects that cause deafness and vestibular dysfunction in humans.
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