Gene regulatory network controlling commitment to ear identity

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DESCRIPTION (provided by applicant): The vertebrate inner is the most complex of the sense organs responsible for hearing and balance. Yet during development it forms from a simple epithelium, the otic placode. During development of the ear, multipotent progenitor cells become progressively restricted in their potential. This process is controlled by regulatory genes whose temporal and spatial expression patterns are tightly regulated in an orchestrated gene regulatory network (GRN). We and others have established a hierarchy of events controlling the specification and determination of inner ear progenitors and identified some of the regulatory genes involved. Based on this information, we have established a preliminary network controlling these processes and designed a molecular screen to identify novel otic specifiers. We have defined co-regulated groups of genes that reflect different stages of ear specification. We will now harness genome sequence information, new technology to monitor changes in the expression of more than 100 genes simultaneously and newly developed bioinformatics tools to build up and verify the preliminary GRN. Specifically we will: " identify new genes responsive to otic inducing signals " establish the epistatic relationships between ear specific transcription factors and signaling components " isolated and characterize enhancers controlling transcription factor expression in the ear and examine direct inputs " predict common upstream regulators for genes in each synexpression group using newly developed algorithms and test the predicted regulators in vivo. This will uncover the basic GRN controlling the specification of inner ear progenitors together with its terminal target genes. In the future, this GRN will serve as a basis for studying protein-protein and protein-DNA interactions to build up a complete network, for quantitative analysis and mathematical modeling of this process, as well as a platform to discover new candidate genes for human disease affecting hearing and balance.