Molecular Basis For The Morphogenesis Of The Inner Ear

Deafness &Other Communication Disorders

Investigators

Linked publications & trials

Abstract

One of our major research interests this year was to identify tissue sources surrounding the inner ear that confer axial information to the ear. We have shown previously from the analysis of Sonic Hedgehog (Shh) mutants that SHH emanating from the midline is important for ventral patterning of the inner ear. However, it is not clear from these studies which component of the midline structure, the notochord or the floor plate, or both, is the source of SHH for the inner ear, since both the notchord and floor plate are absent in the Shh mutants. Using a surgical ablation approach in chicken, we show that either the notochord or the floor plate is sufficient to specify ventral patterning of the inner ear. We also show that dorsal otic tissue is capable of expressing ventral markers when the dorsal-ventral axis of the neural tube is rotated in ovo. These results suggest that signaling from the neural tube is a main component in specifying dorsal-ventral axis of the inner ear. Furthermore, it has been shown that genes expressed in the hindbrain such as kreisler, Hoxa1, and Fgf3, are important for normal inner ear development. However, the downstream targets that normally respond to signaling from the hindbrain are not known. Our data indicate that Gbx2, a transcription factor that is expressed early in otic tissue development, might be an essential downstream target of hindbrain signaling. In continuation of our long-standing interests in the roles of BMPs (Bone morphogenetic proteins) in inner ear development, we are currently generating mice with inner ear specific knock out of Bmp4 in order to evaluate the function of this gene during inner ear development. In addition, to evaluate the possible roles of endogenous BMP antagonists in regulating inner ear development, we investigated the inner ear phenotype of Noggin knock out mice. Noggin is one of the endogenous antagonists for BMPs and its expression domains within the inner ear are in close proximity to Bmp positive domains, suggesting that these ligands regulate each other. In comparison to wild-type mice, the inner ears of Noggin knock out mice are usually small and display abnormal coiling of the cochlea. However, our preliminary analysis indicates that the inner ear defects in Noggin knock out mice is most likely due to defects in the hindbrain rather than a direct loss of Noggin functions within the otic tissue.