MOLECULAR ANALYSES OF TEMPORAL BONE DEVELOPMENT

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The broad goal of this proposal is to study the function of the POU-domain gene, Brain-4 (Brn4), during inner ear development. Mutations in the human ortholog of the Brn4 gene (POU3F4) produce "mixed conductive and sensorineural deafness associated with perilymphatic gusher during stapes surgery" (DFN3; McKusick catalog number 304400). Malformations of both the stapes and the temporal bone occur in these patients. Recently, our laboratory has demonstrated that similar malformations occur in the inner ear of a mouse pedigree containing a targeted "knockout" mutation in the Brn4 gene. Analysis of the ontogeny of developmental abnormalities in this animal model will provide a means to characterize the mechanisms that lead to the mutant phenotype, as well as, insight into the normal development of the temporal bone. The specific aims of this proposal are: 1. To fully characterize the ontogeny of developmental anomalies in mice with a targeted mutation in the Brn4/Pou3f4 gene. 2. To characterize the cellular mechanisms by which developmental defects occur in the Brn4 knockout mice. We propose to test two possible mechanisms that would explain the decreased temporal bone mass observed in the mutant: Hypothesis 1) Brn4 inhibits apoptosis during otic capsule formation, or Hypothesis 2) Brn4 regulates cell proliferation of otic mesenchyme cells. 3. To fully characterize the molecular basis of a Brn4 mutant allele, sex- linked fidget. 4. To characterize otic-specific transcriptional regulatory elements in the Brn4 gene. 5. To undertake functional analyses of auditory function of the Brn4 null pedigree. To address the pathological mechanisms leading to hearing loss of the Brn4 null mutants, we propose to assess auditory function of the Brn4 null pedigree in greater detail.