The aim of this proposal is to study the earliest events in the development of the inner ear. One half of all cases of deafness in children are caused by inherited defects in genes that control the development or function of the inner ear. Despite the clinical significance of the inner ear, little is known about the early development of this sensory organ. The entire inner ear develops from a patch of thickened ectoderm on either side of the hindbrain called the otic placode. The otic placode is believed to be induced by signals from neighboring inducing tissues. We hypothesize that signaling molecules produced by these up-regulate of gene expression.
Specific Aim 1 : Induction of the otic placode is thought to be directly regulated by one or both of two candidate inducing tissues-the hind brain of the cranial paraxial mesoderm. We will test these candidate inducing tissues with responding ectoderm in a neutral tissue culture system (sufficiency experiments). Induction will be assayed using six molecular markers of the otic placode that we have recently identified. Specifc Aim 2: Two members of the fibroblast growth fibroblast growth factor (FGF) family, FGF-2 and FGF-3 have been proposed to play a role in otic placode induction, but no studies to date have rigorously tested the necessity or sufficiency of FGF signaling in this process. Accordingly, we will determine whether FGF signaling is necessary of sufficient for the induction of the otic placode by gain-and-loss of function experiment using pharmacological and dominant-negative inhibitors of FGF signaling, and application of FGF family members in vivo and in vitro.
Specific Aim 3 : We have identified 5 members of the chicken Dix family of homeobox-containing transcription factors, Dix -2,3,4,5 and 6. Several of these genes are expressed in the development of otic placode. We propose that Dix gene function is required to activate otic placode-specific gene expression in cranial ectoderm in response to inducing signals. We will determine whether members of the dix family of transcriptional regulators are necessary for the induction of the otic placode by creating dominantnegative constructs of these five Dix genes and expressing them in otic placode ectoderm
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