Morphogenetic signaling by retinoic acid and its regulation during inner ear development

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Vertebrate inner ear development is sensitive to alterations in retinoic acid (RA) signaling, but the morphogenetic processes that are controlled by RA and its molecular targets are largely unexplored. Whereas mammals co-express three retinaldehyde-dehydrogenases within the inner ear, only Aldh1a3 and Aldh1a2 are present in the zebrafish developing inner ear and in flanking tissues, respectively. It is thus feasible to accomplish a straightforward genetic analysis of RA function in the zebrafish otic vesicle. Our goals are threefold: 1) We will use genetic and chemical genetic methods to examine the hypothesis that RA signaling patterns epithelial projections in the inner ear and is required for the formation of the otic capsule; 2) In a microarray analysis we have identified candidate target genes that are up- and down-regulated by RA signaling; we will characterize their expression profiles and RA-sensitivity in the inner ear and will examine their function by gene knockdown; 3) To advance the visualization and to dissect the cellular dynamics of inner ear morphogenesis, we will develop transgenic zebrafish lines that recapitulate RA-mediated gene activation and the dynamics of RA synthesis within the inner ear in vivo. Together, the proposed studies will unravel the roles of RA-mediated control of gene activity and will allow us to associate molecular genetic interactions with morphological change in the developing inner ear.