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 control the balanced function of tissues at adult ages. The breadth of different tissue responses including in the nervous, sensory, metabolic and endocrine systems, raises a key question concerning the mechanisms that determine the tissue-specificity of thyroid hormone functions. How does thyroid hormone elicit so many different 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 genes, THRB and THRA, encode receptor isoforms that are expressed in different developmental and tissue-specific patterns and mediate many different 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 receptors and of cooperative factors that modify receptor activity in different tissues. Elucidating mechanisms that determine tissue-specific responses to thyroid hormone is a prerequisite for understanding the tissue dysfunction that occurs in human thyroid diseases. The themes of the project employ genetics and genomics as well as molecular biology approaches. The project aims include: 1. Functions of TRb receptors in differentiation and homeostasis. To determine the biological functions of these receptors, we study genetic models in which TRb1 or TRb2 have been tagged to identify cell-specific expression patterns in detail. We have focused on the role of TRb1 in the cochlea and endocrine tissues including the anterior pituitary and adrenal cortex. In the auditory system, TRb1 maintains hearing during adulthood and aging. The findings suggest that thyroid hormone may be a factor that counters age-related hearing loss, which occurs widely in human populations. In the adrenal gland, TRb1 is expressed in a novel, 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 critically control TR activity. Other findings indicate 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. These studies support the proposal that receptor isoforms and deiodinases function in cooperation in a given tissue to determine the timing of the specific response. We also found that membrane transporters for the cellular uptake of thyroid hormone are critical for cochlear development and potentially for the development of other tissues. 3. Target gene specificity of thyroid hormone action in different tissues. How can a receptor bind and regulate a gene in the pituitary but not in the liver? To study this critical question and to investigate tissue-specific factors that determine the specificity of the gene networks in tissues under thyroid hormone control, we have derived genetic models to investigate mechanisms of transcriptional regulation of candidate target genes. These studies involve molecular and genomic approaches, including use of a novel genetic model, a Thrb-b1Cre driver to label and isolate specific cell types for analysis. The study investigates changes in gene expression patterns and genomic DNA binding sites for receptor isoforms in different tissues, with a focus on endocrine (for example, pituitary) and sensory (cochlea) systems.