Tissue-specific functions of thyroid hormone receptors

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Thyroid hormone mediates a remarkable range of actions in many tissues and organs. These actions promote the development of tissues in the fetus and infant and the function of tissues at more mature ages and in adults. The breadth of different responses, including in the nervous, sensory, metabolic and endocrine systems, highlights a key question concerning the mechanisms that determine the tissue-specificity of the functions of thyroid hormone. How does thyroid hormone elicit so many different cellular responses? Thyroid hormone receptors (TR) act as ligand-regulated transcription factors and occupy a key position in the chain of events that elicit a cellular response. Two receptor genes, THRB and THRA, encode receptor isoforms that are expressed in different developmental and tissue-specific patterns and mediate diverse tissue functions. This project investigates the mechanisms that determine the tissue-specific functions of the TRb1 and TRb2 receptor isoforms encoded by the THRB gene. The aim is to reveal the developmental and homeostatic functions of these isoforms and of other cooperative factors that modify the activity of the receptors in different tissues. Elucidating these mechanisms that determine tissue-specific responses to thyroid hormone is a prerequisite for understanding the tissue dysfunction that occurs in human thyroid diseases. We take advantage of genetic, genomic and molecular approaches to investigate: 1. Functions of TRb receptors in differentiation and homeostasis. To determine the biological functions of TRb isoforms, we study genetic models in which TRb1 or TRb2 have been deleted. These studies have identified novel, cell-specific expression patterns of TRb1 in the cochlea and endocrine tissues including the anterior pituitary and adrenal cortex. In the auditory system, we found that TRb1 maintains hearing during adulthood and aging. The findings suggest that thyroid hormone may be a factor that counters age-related hearing loss, a widespread condition in human populations. In the adrenal gland, TRb1 is expressed in a previously unrecognized, sexually-dimorphic, cortical cell population and mediates hypertrophic responses, suggesting direct actions for thyroid hormone in adrenal function. 2. Factors that influence TR activity in tissue-specific fashion. We investigate factors including deiodinase enzymes that activate and inactivate thyroid hormone, as well as plasma membrane transporters that mediate the cellular uptake of thyroid hormone from the circulation into specific cells. We found that in several target tissues (e.g., cochlea, pituitary), deiodinase enzymes provide critical control over TR activity. Recent evidence indicates that tissues such as the retina and the testis are subject to control by type 3 deiodinase, an enzyme that degrades hormone thereby constraining the stimulation of the tissue. The findings support the proposal that specific receptor isoforms and deiodinases function in close cooperation in a given tissue to determine the timing of the specific response. We also found that membrane transporters that control the cellular uptake of thyroid hormone are critical for cochlear development and potentially for the development of other tissues. 3. Target genes for TRb isoforms in natural tissues. To study this critical question regarding the mechanisms by which thyroid hormone stimulates cellular differentiation and function, we have derived genetic models to investigate mechanisms of transcriptional regulation by TRb receptors of candidate target genes. These studies involve a range of molecular and genomic approaches, including use of novel genetic models, to identify changes in gene expression patterns and genomic DNA binding sites for these receptor isoforms in different tissues, with a focus on endocrine (pituitary) and sensory (cochlea) systems.