The Thyroid Hormone Receptor Gene: Structure and Functions in the Brain and Sensory Systems (original) (raw)
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Multigenic control of thyroid hormone functions in the nervous system
Molecular and Cellular Endocrinology, 2008
Thyroid hormone (TH) has a remarkable range of actions in the development and function of the nervous system. A multigenic picture is emerging of the mechanisms that specify these diverse functions in target tissues. Distinct responses are mediated by α and β isoforms of TH receptor which act as ligand-regulated transcription factors. Receptor activity can be regulated at several levels including that of uptake of TH ligand and the activation or inactivation of ligand by deiodinase enzymes in target tissues. Processes under the control of TH range from learning and anxiety-like behaviour to sensory function. At the cellular level, TH controls events as diverse as axonal outgrowth, hippocampal synaptic activity and the patterning of opsin photopigments necessary for colour vision. Overall, TH coordinates this variety of events in both central and sensory systems to promote the function of the nervous system as a complete entity.
Identification of a novel human thyroid hormone receptor β isoform as a transcriptional modulator
Biochemical and Biophysical Research Communications, 2010
Thyroid hormone exerts a pleiotropic effect on development and homeostasis. A novel thyroid hormone receptor b isoform (hereafter referred to as TRb4) was cloned using PCR from a human pituitary cDNA library as a template. Analysis of the PCR products revealed a 137-bp insertion, which contains a stop codon in the middle, between the 5th and 6th exons that encode the ligand-binding domain of TRb. The corresponding sequence of this insertion exists within the 5th intron of the human TRb gene and consensus splice sequences were found at the junction sites. RACE analysis revealed that TRb4 is a carboxylterminal splicing variant of TRb1. RT-PCR and Northern blot analyses indicate that TR b4 mRNA is expressed in various human tissues, and especially abundant in testis and skeletal muscle. The TRb4 protein was unable to bind thyroid hormone (T3) and transient transfection assays demonstrate that TRb4 construct does not mediate T3-dependent gene regulation. TRb4 weakly but significantly inhibited transcription mediated by functional TR. Thus, this novel isoform may modulate hormone action as an endogenous antagonist in the tissue or cellular context.
Molecular Endocrinology, 2007
The Thrb gene, encoding thyroid hormone receptor  (TR), serves key roles in endocrine regulation and the development of the senses of hearing and color vision. The versatile functions of this gene depend upon its expression of distinct receptor isoforms by differential promoter activation. The TR2 isoform has a particularly specialized distribution including in the anterior pituitary and cochlea. TR2 is also found in immature cone photoreceptors where it has a unique role in programming the expression pattern of opsin photopigments that mediate color vision. Given the importance of precise, tissue-specific expression for the function of TR2, we investigated the genomic control elements that direct this expression in vivo using lacZ reporter transgenes in mice. The TR2 promoter region is sufficient for cochlear expression, whereas a complex intron control region is necessary for pituitary and retinal expression. In the retina, the intron region directs peak expression in the embryo in postmitotic, immature cones. The retinal control region is further subdivided into domains that specify and amplify expression, respectively, indicating that timely, conespecific expression reflects an integrated response to complex signals. The mammalian Thrb gene has therefore incorporated several mechanisms into a multifunctional intron control region that regulates developmental induction of the distant promoter. This specialized genomic organization underlies the unique expression pattern and functions of TR2. (Molecular
A temporary compendium of thyroid hormone target genes in brain
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2015
a b s t r a c t 6 30 31 33 roxine, or T4, its less active precursor) play an important function in 34 fetal and adult brain. During neurodevelopment they are required for 35 proper neuronal and glial differentiation, neuronal migration, and mye-36 lin formation. Thyroid hormone deficiency during human development 37 may cause irreversible mental retardation and variable degrees of 38 neurological impairment. In adults T3 is necessary for neural stem cell 39 proliferation and differentiation, and hypothyroidism is often associated 40 with mood disorders. T3 acts on gene expression mainly, if not only, 41 by binding to nuclear receptors (TRα1, TRβ1 and TRβ2, collectively 42 TR) encoded by the two Thra and Thrb genes and which act as ligand-43 dependent transcription factors. TR forms heterodimers with RXR, 44 which bind to DNA in a T3 independent manner. In vitro experiments 45 suggest that binding could occur on several types of response ele-46 ments, constituted by doublets of the half-site AGGCTA, or on DNA 47 elements bearing only limited similarity to this consensus. This binding 48 to regulatory elements of gene promoters induces changes of expres-49
Thyroid hormone regulated genes in cerebral cortex development
Journal of Endocrinology, 2016
The physiological and developmental effects of thyroid hormones are mainly due to the control of gene expression after interaction of T3with the nuclear receptors. To understand the role of thyroid hormones on cerebral cortex development, knowledge of the genes regulated by T3during specific stages of development is required. In our laboratory, we previously identified genes regulated by T3in primary cerebrocortical cells in culture. By comparing these data with transcriptomics of purified cell types from the developing cortex, the cellular targets of T3can be identified. In addition, many of the genes regulated transcriptionally by T3have defined roles in cortex development, from which the role of T3can be derived. This review analyzes the specific roles of T3-regulated genes in the different stages of cortex development within the physiological frame of the developmental changes of thyroid hormones and receptor concentrations in the human cerebral cortex during fetal development. ...