' Understanding the early development of sensory placodes and its underlying molecular and genetic control is essential for progress in the alleviation of genetic-determined sensory perception disorders and congenital diseases. Our long term goal is to understand how cells are specified to form sensory organs. Investigations are proposed to study sensory placode formation in the relatively small and simple zebrafish embryo. This species has many attributes for both developmental and genetic studies, and can serve as model system for understanding the development of sensory organs in all vertebrates, including humans. Specifically: 1. We will analyze the roles of fgf-receptors in the development of the otic and olfactory placodes. Fgf- signals appear to be the main inducers of sensory placodes, yet less is known about the contol of expression and individual functions of the receptors, an integral part of this inductive interaction. 2. The transcription factors dlx3b/4b and foxil are required intrinsically in sensory placodes for their normal development. Genetic evidence suggests that they are involved in regulating FGF-signaling, yet it is not known how they do so, which we propose to elucidate. Fgf-signals play major roles in many biological processes, including human diseases, and understand!ngthe roles co-factors and regulators of this will lead to important insights. 3. We will examine the function and regulation of genes specifically expressed in sensory placodes. The genes to be studied are potential targets of dlx3b/4b. These studies will lead to new insights in tissue specific control of gene expression, lead to the identification of novel genes involved in sensory placode development. 4. We will analyze the function of two tbx2 genes in ear development. These genes are known to integrate signals form different pathways, yet the precise mechanisms by which they do so are unclear. Members of this tbx family are involved in mammary tumorigenesis, and our studies may shed additional light on this important role in human health. Hearing loss in humans affects about 1/1000 individuals, yet a lot remains to be learned about the genes that control the development and function of the inner ear. Our previous studies have lead to the characterization of novel genes involved in this process, some of which, such as the claudin gene, are involved in human disease, validating our overall approach. The study of these genes in the zebrafish model will allow us a better understanding of the precise functions of these genes and potential avenues for disease treatments. ? ? ?
