Deafness and hearing loss due to damage of the inner ear and cochlear nerve remain as major incurable disorders today. Also of much concern are congenital forms of damage, since the resulting hearing impairment profoundly disturbs the development of communication skills and learning. These conditions are associated with degeneration and reorganization of the central auditory pathways, To understand better these conditions, we need to acquire some insight into the factors that account for axonal growth and synapse formation in the development of the auditory pathway, since the same genetic factors are likely to be involved in these processes during normal development, congenital malformation, and plastic changes in the mature nervous system. This research aims to elucidate the cellular interactions leading to the assembly of the sensorineural structures of the inner ear and the connections with the central auditory pathway. The approach is to study the role of certain key molecules (growth factors and their receptors) in the differentiation of the cochlear ganglion cells by microscopic observations of their morphogenesis during normal development. Experimental perturbations of their embryonic precursors and their target tissues, i.e., the sensory epithelium and cochlear nucleus, will be carried out to test genetic hypotheses concerning the role of these key molecules. Cell cultures of the precursors of the ear and acoustic nuclei of chicken and mouse embryos and neonates are used to characterize the cellular interactions. Induced genetic mutants with single gene deletions or overexpression models are compared with normal mice. Experiments are designed to reveal key factors involved in these interactions and the loci of their actions at the molecular level. Antibodies and in situ hybridization will be used for localizing such molecules to specific cell types at the critical stages of the developmental process in situ. Experimental perturbations of cultured mouse cochlear ganglion cells, including treatment with growth factors, antibodies, and transfected nucleic acids will be used to evaluate their interactions with the cochlear nucleus and inner ear of embryonic and neonatal animals. Co-cultures of sensory neuronal precursors and otic epithelium from normal and genetically modified mouse embryos will be used to determine how cells with specific genetic alterations are affected. Ultimately these findings should provide a rational basis for developing new therapies.