Congenital hearing deficits affect 1 out of every 4000 births. In many cases the cause of these deficits is the incomplete development of the hair cells in the organ of Corti. The factors that influence the formation of the organ of Corti, and in particular the determination and differentiation of cells as hair cells are largely unknown. However, the results of several studies suggest that members of the steroid/thyroid family of ligands and receptors, and specifically retinoic acid and thyroid hormone, may plan key roles in the development of cells as hair cells. The experiments outlined in this proposal will test several hypotheses from a model of hair cell development in which activation of retinoic acid receptor and thyroid receptors by their specific ligands leads to upregulation of genes that induce progenitor cells to become determined (specified) to differentiate as hair cells. The experiments will address the following groups of questions: 1. What are the patterns of expression of the different retinoic acid and thyroid receptors ina the developing cochlear sensory epithelium: Are other members of the steroid/thyroid family of receptors which can inhibit the response of retinoic acid receptors/thyroid receptors also expressed in regions of the developing sensory epithelium? 2. Is activation of retinoic acid receptors by retinoic acid necessary for the determination (specification) of cells as hair cells? Is activation of thyroid receptors by thyroid hormone also necessary for the determination of hair cells? 3. What other gene products may be involved in the determination of cells as hair cells? An understanding of the factors that influence the determination and differentiation of cells as hair cells is essential for the identification and treatment of congenital hearing deficits, as well as for the development of potential regenerative therapies.
| Campos-Barros, A; Amma, L L; Faris, J S et al. (2000) Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing. Proc Natl Acad Sci U S A 97:1287-92 |
| Zhang, N; Martin, G V; Kelley, M W et al. (2000) A mutation in the Lunatic fringe gene suppresses the effects of a Jagged2 mutation on inner hair cell development in the cochlea. Curr Biol 10:659-62 |
| Raz, Y; Kelley, M W (1999) Retinoic acid signaling is necessary for the development of the organ of Corti. Dev Biol 213:180-93 |
