Thyroid hormone mediates a remarkable range of functions in many tissues and organ systems. These functions are important both in development and adult homeostasis. The breadth of responses raises a key question concerning the mechanisms that determine the nature, time and place of a given response to thyroid hormone. How does one 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 produce the cellular response. Two receptor genes, Thrb and Thra, encode several TR isoforms that are expressed in different developmental and tissue-specific patterns. Thus, the ability to express a given receptor isoform in a particular tissue provides a means of conferring a specific biological response. This project investigates the mechanisms that direct the unique expression patterns of different TR isoforms as a mechanism that determines specific functions of thyroid hormone. This project also investigates specific developmental and homeostatic functions for the different receptor isoforms encoded by the Thra and Thrb genes. Progress: 1. The Thrb gene has a large and complex structure, spanning about 400 kb on human chromosome 3 or mouse chromosome 14. Our studies have mapped functional control regions of the Thrb gene in mouse models. We are pursuing studies to investigate the mechanisms mediated by these regions that direct tissue-specific expression of the TRb receptor isoforms including in the pituitary, cochlea and retina. The unusual multi-functional nature of these control regions provides a model system of biological importance in which to investigate how transcriptional mechanisms regulate chromatin structure and gene activity in different tissues. To investigate the potential significance of genomic control regions in determining the thyroid hormone response in human tissues, the control regions of the mouse Thrb gene have been compared with the corresponding regions of the human THRB gene (collaboration with Dr F. Celi, NIDDK). 2. Functions of TRa1 and TRb isoforms in tissue differentiation and homeostasis. We continue to investigate tissue- and cell-specific functions or the different TR isoforms expressed by the Thra and Thrb genes in mamalian model systems. To determine the specific biological functions for the TRb1 isoform, we are studying a mouse model in which TRb1 has been specifically deleted while leaving the TRb2 isoform intact. This model also incoporates a marker gene cassette in the TRb1-specific exon that allows detailed analysis of the cell-specific expression of this isoform in different tissues. 3. Target genes for TRb isoforms in tissue development and homeostasis. To study this critical question regarding the mechanisms by which thyroid hormone produces changes in cellular differentiation or function, we are continuing in our investigation of candidate target genes for TRb isoforms. These studies involve the use of a variety of molecular approaches to identify changes in gene expression patterns and candidate binding sites for these receptor isoforms in the genome in different tissues.

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8
Fiscal Year
2014
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U.S. National Inst Diabetes/Digst/Kidney
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Sharlin, David S; Ng, Lily; Verrey, François et al. (2018) Deafness and loss of cochlear hair cells in the absence of thyroid hormone transporters Slc16a2 (Mct8) and Slc16a10 (Mct10). Sci Rep 8:4403
Martinez, M Elena; Karaczyn, Aldona; Stohn, J Patrizia et al. (2016) The Type 3 Deiodinase Is a Critical Determinant of Appropriate Thyroid Hormone Action in the Developing Testis. Endocrinology 157:1276-88
Ng, Lily; Cordas, Emily; Wu, Xuefeng et al. (2015) Age-Related Hearing Loss and Degeneration of Cochlear Hair Cells in Mice Lacking Thyroid Hormone Receptor ?1. Endocrinology 156:3853-65
Peeters, R P; Ng, L; Ma, M et al. (2015) The timecourse of apoptotic cell death during postnatal remodeling of the mouse cochlea and its premature onset by triiodothyronine (T3). Mol Cell Endocrinol 407:1-8
Huang, Chen-Che Jeff; Kraft, Cary; Moy, Nicole et al. (2015) A Novel Population of Inner Cortical Cells in the Adrenal Gland That Displays Sexually Dimorphic Expression of Thyroid Hormone Receptor-?1. Endocrinology 156:2338-48
Bianco, Antonio C; Anderson, Grant; Forrest, Douglas et al. (2014) American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 24:88-168
Peeters, Robin P; Hernandez, Arturo; Ng, Lily et al. (2013) Cerebellar abnormalities in mice lacking type 3 deiodinase and partial reversal of phenotype by deletion of thyroid hormone receptor ?1. Endocrinology 154:550-61
Forrest, Douglas; Visser, Theo J (2013) Thyroid hormone signaling. Biochim Biophys Acta 1830:3859
Forrest, Douglas; Wess, Jurgen (2013) A heartfelt response: new thyroid hormone-sensitive neurons in the hypothalamus. J Clin Invest 123:117-20
Alberobello, Anna Teresa; Congedo, Valentina; Liu, Hong et al. (2011) An intronic SNP in the thyroid hormone receptor ýý gene is associated with pituitary cell-specific over-expression of a mutant thyroid hormone receptor ýý2 (R338W) in the index case of pituitary-selective resistance to thyroid hormone. J Transl Med 9:144

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