Thyroid hormone is necessary for the development of the nervous system. A lack of thyroid hormone in early development in the mammalian fetus or neonate can result in mental retardation and other neurological defects, including deafness. Hearing is one of the most sensitive functions that is subject to control by thyroid hormone yet despite the importance of this hormone for hearing, its actions in promoting the development of the auditory system are incompletely understood. The goals of the project are to elucidate the functions of thyroid hormone in the auditory system and to identify the genes that mediate these functions. Progress: 1. Study of a mouse strain with a novel mutation in the Thra thyroid hormone receptor gene receptor has revealed a deafness phenotype. Preliminary data indicate a phenotype that differs from the cochlear phenotype previously associated with mutations in the Thrb gene, suggesting possible independent functions for the Thra and Thrb genes in the development of hearing (collaboration with Dr. S-Y. Cheng, NCI, Dr. Matt Kelley, NIDCD). 2. Recent data show that genes encoding deiodinases, thyroid hormone-metabolizing enzymes, are important for hearing. The results suggest that changing patterns of expression of distinct deiodinase genes encoding both activating and inactivating enzymes (Dio2 and Dio3, respectively) produce deafness phenotypes in mouse genetic models. The findings suggest that these enzymes are important within the target tissues of the auditory system for modifying precisely where and when thyroid hormone acts in triggering the correct onset of hearing. Thus, the action of thyroid hormone upon the auditory system incorporates both endocrine and paracrine components of control. 3. A gene encoding an extracellular matrix protein was detected in a screen for cochlear genes that may be abnormally expressed in deaf mice lacking a thyroid hormone receptor. This gene has been studied as a candidate gene that lies downstream of the thyroid hormone signal in auditory development. Preliminary data from a mouse model suggest that the gene is required for normal auditory function.