Nuclear receptors are ligand-regulated transcription factors and serve many biological roles. One focus of our work has been on the thyroid hormone receptor (TR) family, encoded by the Thra and Thrb genes. Thyroid hormone has many functions in development and in adult physiology and targeted mutagenesis has been valuable in determining the role of different TR isoforms in endocrine function, growth and brain development. Our studies also indicate unexpectedly critical roles in the sensory systems for hearing and color vision. Current research areas include the question of how the correct timing of TR activity in development is determined. Specifically, we are addressing this in the auditory and visual systems, which are physiologically important systems and where we already know that TR isoforms are critically involved. The auditory system is highly sensitive to thyroid hormone and human congenital thyroid disorders are associated with the risk of hearing loss. The deletion of one or more receptor genes in genetic models has shown that TRbeta isoforms, encoded by the Thrb gene, are necessary for hearing. Recently, we found that deiodinases, which are enzymes that control the local availability of T3 the ligand for the TR, provide a powerful tissue-specific control in the development of the auditory system. In particular, we obtained evidence that D2 deiodinase in the cochlea itself confers upon this auditory sensory organ the ability to stimulate its own maturation through the local amplification of T3 signals and thereby, the correct onset of hearing. In the retina, cone photoreceptors with sensitivity to blue and green wavelengths mediate color vision. However, the cone differentiation pathway and the means by which blue and green cone subtypes are generated are poorly understood. We found previously that the specialized TRbeta2 isoform has a critical role in the diversification of cones into green- or blue-light sensitive sub-types. To investigate the signals that stimulate the first, committal steps in the cone differentiation pathway, we recently identified the elements of the Thrb gene that direct the photoreceptor-specific expression of TRbeta2. Separate genomic elements direct expression of TRbeta2 in the cochlea, pituitary and retina. The retinal-specific region is conserved in mammalian species and provides a valuable means of studying the transcription signals that trigger the earliest, determinative steps in the cone pathway. The conserved structure and expression of TRbeta isoforms in vertebrate species suggest that one of the most fundamental roles of the Thrb gene is in determining the sensory properties of hearing and color vision.
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