Proper patterning of the inner ear requires instructive signaling from surrounding tissues including the hindbrain, mesoderm and notochord. The molecular mechanisms underlying these inductive events are largely unknown. One of our major accomplishments this year (in collaboration with Dr. Douglas Epstein at the University of Pennsylvania) was to demonstrate that Sonic Hedgehog (Shh) is an important signal in specifying the inner ear. The ventral portion of the neural tube (floor plate) and the notochord are thought to be the primary sources of SHH for the inner ear. In Shh knock out mice, ventral inner ear structures such as the saccule and cochlea fail to develop. Medial and lateral structures such as the endolymphatic duct and lateral canal, appear to be specified initially but fail to develop at later stages. The process of neuroblast delamination from the anterior region of the otocyst to form the cochleovestibular ganglion is also affected in the Shh mutants. Gene expression analyses of Shh knock out mutant mice as well as transgenic mice that ectopically express Shh in the otocyst show that several genes such as Ngn1, Pax2, Otx2, Tbx1, and Brn4 are likely downstream targets of SHH. Another long-standing interest in the laboratory is to investigate the role of Bone Morphogenetic Proteins (BMPs) in the developing inner ear. Various Bmps are expressed in the developing otic epithelium and regions of surrounding mesenchyme during different stages of development. Previously, we have shown that BMPs are important for the semicircular canal development as well as the formation of the otic capsule. During this year, by correlating the expression patterns of various BMPs with the localization of cells responding to them, we postulated that BMPs mediate epithelial to mesenchymal interactions in specific regions of the inner ear such as the endolymphatic duct and semicircular canals. Furthermore, the formation of sensory and non-sensory components of the inner ear are most likely coupled during development, even though the molecular mechanisms involved in this coordination are largely unknown. FGF-3 and 10 (Fibroblast growth factor) are expressed in the presumptive sensory organs while one of their receptors, FGFR2-IIIb, is primarily expressed in the non-sensory epithelium. These patterns suggest that FGFs in the sensory organ could play such a role in coordinating sensory and non-sensory development. Using a recombinant avian retrovirus encoding FGF-3 or beads soaked with FGF-2, we showed that FGFs promote canal development in the chicken inner ear. These effects of FGFs are mediated by induction of Bmp2 in the canal pouch region, thus identifying a molecular pathway whereby sensory tissue can induce non-sensory development.
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