Our laboratory studies the development and function of the inner ear, using the techniques of cell and molecular biology. We are interested in the developmental determination of cochlear cell phenotype, hair cell protection and regeneration, and the molecular basis transduction including cochlear mechanics, mechanotransduction channels, and outer hair cell electromotility.
REGULATION OF SENSORY AND NEURONAL CELL PHENOTYPE. Among the factors contributing to the development of sensory cells (hair cells) and primary afferent neurons in the inner ear are a number of transcription factors. The POU- domain factor Brn-3.1 is required for the differentiation of hair cells from their parent cells in the sensory epithelium, as shown by knockout studies. Similarly, the POU-domain factor Brn-3.0 is required for the normal proliferation and migration of primary sensory neurons. The genes encoding these factors offer opportunities to study the regulation of differentiation in these two important cell types, to characterize promoters specific to cochlear cells, and to identify new genes that are specifically involved in the development and function of the inner ear.
CONTROL OF COCHLEAR INNERVATION. Patterns of innervation in the sensory epithelium of the cochlea appear to be controlled by a combination of extracellular matrix molecules and growth factors. In particular, fibronectin is present in the path of ingrowing neurites, while the sensory cells produce several neurotrophic and neurotropic growth factors. We have found that neurites from cochlear sensory neurons can be stimulated to form connections with cells engineered to secrete such factors. Also, the growth of these neurites can be altered by dominant negative mutants of the integrin receptors for extracellular matrix molecules. Our group is actively characterizing both forms of innervation control.
A SARCOMERIC MYOSIN IN A NON-MUSCLE TISSUE. We have recently found that a sarcomeric myosin heavy chain (MHC) is expressed at high levels in a thin membrane that separates two fluid compartments along the length of the cochlea. This is the only non-muscle tissue in which a sarcomeric myosin is known to be expressed. MHC expression is graded along the length of the cochlea, and ceases abruptly as this membrane enters the vestibular portion of the inner ear. We are evaluating the function of this MHC in the cochlea, and contrasting the regulation of this gene in non-sarcomeric cells with more traditional regulation in muscle.
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Fina, M., and Ryan, A.F. (1994). Expression of mRNAs encoding subunit isoforms of the Na,K-ATPase in the vestibular labyrinth of the rat. Cell. Molec. Neurosci. 5: 604-613.
Luo, L., Brumm, D., and Ryan, A.F. (1995). Distribution of non-NMDA glutamate receptor mRNAs in the developing rat cochlea. J. Comp. Neurol. 361: 372-382.
Housley, G.D., Greenwood, D., Bennett, T., and Ryan, A.F. (1995). Identification of a short form of the P2xR1-purinoceptor subunit produced by alternative splicing in the pituitary and cochlea. Bioche
Low, W., Dazert, S., Baird, A., and Ryan, A.F. (1996). Basic fibroblast growth factor (FGF-2) protects rat cochlear hair cells in organotypical culture from aminoglycoside injury. J. Cell Physiol. 167
Erkman, L., McEvilly, R.J., Luo, L., Ryan, A.E., Hoosmand, F., O'Connell, S.M., Keithley, E.M., Rappaport, D.H., Ryan, A.F., and Rosenfeld, M.G. (1996). Requirement for Brn-3.1 and Brn-3.2 in auditory
Merati, A., Bodine, S.C., Bennett, T., Jung, H.H., Furuta, H., and Ryan, A.F. (1996). Identification of a novel myosin heavy chain gene expressed in the rat larynx. Biochim. Biophys. Acta 1306: 153-15
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