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P R Larsen - One of the best experts on this subject based on the ideXlab platform.
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Enhancement of thyroid Hormone receptor isoform specificity by insertion of a distant half-site into a thyroid Hormone Response element.
Endocrinology, 1996Co-Authors: Ann Marie Zavacki, C Y Zhang, John W. Harney, P R LarsenAbstract:The two isoforms of thyroid Hormone receptor (TR), alpha and beta, are highly homologous, except in the amino-terminal domain. Specific physiological roles for the receptor isoforms have not yet been defined. In transient transfection assays, TRalpha is twice as potent a thyroid Hormone (T3)-dependent transactivator as TRbeta on a number of thyroid Hormone Response elements (TREs). Using chimeras of TRalpha and -beta, we have determined that the higher transactivation by TRalpha requires the entire ligand-binding domain. The amino-terminal and DNA-binding domains of the two isoforms are interchangeable. These studies were facilitated by the use of a synthetic TRE composed of a direct repeat separated by 4 bp which also included a third half-site 19 bp 3' to this on the opposite strand. In the presence of T3, this TRE confers a 5-fold higher Response to TRalpha than to TRbeta, but there is no difference in expression without T3. Functional studies indicate that all three half-sites are needed for the incre...
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enhancement of thyroid Hormone receptor isoform specificity by insertion of a distant half site into a thyroid Hormone Response element
Endocrinology, 1996Co-Authors: Ann Marie Zavacki, C Y Zhang, John W. Harney, P R LarsenAbstract:The two isoforms of thyroid Hormone receptor (TR), alpha and beta, are highly homologous, except in the amino-terminal domain. Specific physiological roles for the receptor isoforms have not yet been defined. In transient transfection assays, TRalpha is twice as potent a thyroid Hormone (T3)-dependent transactivator as TRbeta on a number of thyroid Hormone Response elements (TREs). Using chimeras of TRalpha and -beta, we have determined that the higher transactivation by TRalpha requires the entire ligand-binding domain. The amino-terminal and DNA-binding domains of the two isoforms are interchangeable. These studies were facilitated by the use of a synthetic TRE composed of a direct repeat separated by 4 bp which also included a third half-site 19 bp 3' to this on the opposite strand. In the presence of T3, this TRE confers a 5-fold higher Response to TRalpha than to TRbeta, but there is no difference in expression without T3. Functional studies indicate that all three half-sites are needed for the increased responsiveness to TRalpha, but gel shift analyses show no striking differences in the ratios of TRalpha to TRbeta binding compared to other wild-type TREs. These results suggest that important functional differences are present in the ligand-binding domain of TRalpha and -beta despite their high homology.
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A NOVEL RETINOID X RECEPTOR-INDEPENDENT THYROID Hormone Response ELEMENT IS PRESENT IN THE HUMAN TYPE 1 DEIODINASE GENE
Molecular and cellular biology, 1995Co-Authors: N Toyoda, Ann Marie Zavacki, John W. Harney, Ana Luiza Maia, P R LarsenAbstract:We identified two thyroid Hormone Response elements (TREs) in the 2.5-kb, 5'-flanking region of the human gene encoding type 1 iodothyronine deiodinase (hdio1), an enzyme which catalyses the activation of thyroxine to 3,5,3'-triiodothyronine (T3). Both TREs contribute equally to T3 induction of the homologous promoter in transient expression assays. The proximal TRE (TRE1), which is located at bp -100, has an unusual structure, a direct repeat of the octamer YYRGGTCA hexamer that is spaced by 10 bp. The pyrimidines in the -2 position relative to the core hexamer are both essential to function. In vitro binding studies of TRE1 showed no heterodimer formation with retinoid X receptor (RXR) beta or JEG nuclear extracts (containing RXR alpha) and bacterially expressed chicken T3 receptor alpha 1 (TR alpha) can occupy both half-sites although the 3' half-site is dominant. T3 causes dissociation of TR alpha from the 5' half-site but increases binding to the 3' half-site. Binding of a second TR to TRE1 is minimally cooperative; however, no cooperativity was noted for a functional mutant in which the half-sites are separated by 15 bp, implying that TRs bind as independent monomers. Nonetheless, T3 still causes TR dissociation from the DR+15, indicating that dissociation occurs independently of TR-TR contact and that rebinding of a T3-TR complex to the 3' half-site occurs because of its slightly higher affinity. A distal TRE (TRE2) is found at bp -700 and is a direct repeat of a PuGGTCA hexamer spaced by 4 bp. It has typical TR homodimer and TR-RXR heterodimer binding properties. The TRE1 of hdio1 is the first example of a naturally occurring TRE consisting of two relatively independent octamer sequences which do not require the RXR family of proteins for function.
Graham R. Williams - One of the best experts on this subject based on the ideXlab platform.
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Regulation of fibroblast growth factor receptor-1 (FGFR1) by thyroid Hormone: identification of a thyroid Hormone Response element in the murine Fgfr1 promoter.
Endocrinology, 2007Co-Authors: Patrick J. O’shea, Celine J. Guigon, Graham R. Williams, Sheue-yann ChengAbstract:T(3) is essential for normal skeletal development, acting mainly via the TRalpha1 nuclear receptor. Nevertheless, the mechanisms of T(3) action in bone are poorly defined. Fibroblast growth factor receptor-1 (FGFR1) is also essential for bone formation. Fgfr1 expression and activity are positively regulated by T(3) in osteoblasts, and in mice that harbor a dominant negative PV mutation targeted to TRalpha1 or TRbeta, Fgfr1 expression is sensitive to skeletal thyroid status. To investigate mechanisms underlying T(3) regulation of FGFR1, we obtained primary calvarial osteoblasts from wild-type and TRbeta(PV/PV) littermate mice. T(3) treatment increased Fgfr1 expression 2-fold in wild-type cells, but 8-fold in TRbeta(PV/PV) osteoblasts. The 4-fold increased T(3) sensitivity of TRbeta(PV/PV) osteoblasts was associated with a markedly increased ratio of TRalpha1:TRbeta1 expression that resulted from reduced TRbeta1 expression in TRbeta(PV/PV) osteoblasts compared with wild-type. Bioinformatics and gel shift studies, and mutational analysis, identified a specific TR binding site 279-264 nucleotides upstream of the murine Fgfr1 promoter transcription start site. Transient transfection analysis of a series of Fgfr1 promoter 5'-deletion constructs, of a mutant reporter construct, and a series of heterologous promoter constructs, confirmed that this region of the promoter mediates a TR-dependent transcriptional Response to T(3). Thus, in addition to indirect regulation of FGFR1 expression by T(3) reported previously, T(3) also activates the Fgfr1 promoter directly via a thyroid Hormone Response element located at positions -279/-264.
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the rat thyroid Hormone receptor tr δβ3 displays cell tr isoform and thyroid Hormone Response element specific actions
Endocrinology, 2007Co-Authors: Clare B. Harvey, Paul M. Yen, Padma Maruvada, J Duncan H Bassett, Graham R. WilliamsAbstract:The THRB gene encodes the well-described thyroid Hormone (T3) receptor (TR) isoforms TRβ1 and TRβ2 and two additional variants, TRβ3 and TRΔβ3, of unknown physiological significance. TRβ1, TRβ2, and TRβ3 are bona fide T3 receptors that bind DNA and T3 and regulate expression of T3-responsive target genes. TRΔβ3 retains T3 binding activity but lacks a DNA binding domain and does not activate target gene transcription. TRΔβ3 can be translated from a specific TRΔβ3 mRNA or is coexpressed with TRβ3 from a single transcript that contains an internal TRΔβ3 translation start site. In these studies, we provide evidence that the TRβ3/Δβ3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TRβ3 with other TR isoforms and investigated mechanisms of action of TRΔβ3 at specific thyroid Hormone Response elements (TREs) in two cell types. TRβ3 was the most potent isoform, but TR potency was TRE dependent. TRΔβ3 acted as a cell-specific and TRE-dependent modulator of TRβ3 w...
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The rat thyroid Hormone receptor (TR) Δβ3 displays cell-, TR isoform-, and thyroid Hormone Response element-specific actions
Endocrinology, 2007Co-Authors: Clare B. Harvey, Paul M. Yen, J. H. Duncan Bassett, Padma Maruvada, Graham R. WilliamsAbstract:The THRB gene encodes the well-described thyroid Hormone (T3) receptor (TR) isoforms TRbeta1 and TRbeta2 and two additional variants, TRbeta3 and TRDeltabeta3, of unknown physiological significance. TRbeta1, TRbeta2, and TRbeta3 are bona fide T3 receptors that bind DNA and T3 and regulate expression of T3-responsive target genes. TRDeltabeta3 retains T3 binding activity but lacks a DNA binding domain and does not activate target gene transcription. TRDeltabeta3 can be translated from a specific TRDeltabeta3 mRNA or is coexpressed with TRbeta3 from a single transcript that contains an internal TRDeltabeta3 translation start site. In these studies, we provide evidence that the TRbeta3/Deltabeta3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TRbeta3 with other TR isoforms and investigated mechanisms of action of TRDeltabeta3 at specific thyroid Hormone Response elements (TREs) in two cell types. TRbeta3 was the most potent isoform, but TR potency was TRE dependent. TRDeltabeta3 acted as a cell-specific and TRE-dependent modulator of TRbeta3 when coexpressed at low concentrations. At higher concentrations, TRDeltabeta3 was a TRE-selective and cell-specific antagonist of TRalpha1, -beta1, and -beta3. Both TRbeta3 and TRDeltabeta3 were expressed in the nucleus in the absence and presence of Hormone, and their actions were determined by cell type and TRE structure, whereas TRDeltabeta3 actions were also dependent on the TR isoform with which it interacted. Analysis of these complex Responses implicates a range of nuclear corepressors and coactivators as cell-, TR isoform-, and TRE-specific modulators of T3 action.
Ronald J Koenig - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Hormone Response element sequence and the recruitment of retinoid X receptors for thyroid Hormone responsiveness.
The Journal of biological chemistry, 2000Co-Authors: Ronald J KoenigAbstract:Thyroid Hormone receptors (TRs) are transcription factors that bind to thyroid Hormone Response elements (TREs) in the regulatory regions of target genes. TRs are thought to activate transcription primarily as heterodimers with retinoid X receptors (RXRs), with RXR binding upstream to the two directly repeated half-sites in a typical TRE. However, given that TRs and RXRs prefer to bind to different DNA sequences (T(A/G)AGGTCA and GGGGTCA), we postulate that only certain TREs require RXR-TR heterodimerization, depending on the TRE sequence. We have tested this hypothesis by comparing in Saccharomyces cerevisiae the functional activity of TR +/- RXR on 10 naturally occurring mammalian TREs. S. cerevisiae was used as a model system because yeast lack endogenous nuclear receptors and thus can be manipulated to express TRs and/or RXRs. We first studied ligand-independent reporter gene activation, which reflects the activity of the activator function 1 (AF-1) domain. The 10 TREs formed a continuous spectrum from being fully dependent on RXR for TR AF-1 activity to being essentially independent of RXR. Relative independence of RXR generally was seen when the TRE upstream half-site has a TA or TG 5' to the core hexamer. Gel mobility shift assays revealed that functional independence of RXR correlates with the strong binding of TR alone, whereas more RXR dependence correlates with higher binding of RXR-TR heterodimers. Restoration of ligand-dependent (AF-2 domain) reporter gene activation was achieved by expression of the coactivator TIF2. This ligand-induced stimulation was stronger in the presence of TR alone than with RXR plus TR, suggesting a preference for TIF2 activation of TR homodimers. Overall the data support the notion that the TRE sequence plays an important role in determining the nuclear Hormone receptor and coactivator requirements for TR action.
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thyroid Hormone Response element architecture affects corepressor release from thyroid Hormone receptor dimers
Journal of Biological Chemistry, 1998Co-Authors: David P Olson, Baolin Sun, Ronald J KoenigAbstract:Abstract Thyroid Hormone receptors are ligand-modulated transcription factors that can repress or activate transcription depending upon the absence or presence of thyroid Hormone and the nature of the Hormone Response element to which the receptors are bound. The ability of thyroid Hormone receptors to repress transcription in the absence of ligand is thought to be due to associations with nuclear Hormone receptor corepressors. Ligand binding by the thyroid Hormone receptor is believed to dissociate these corepressors and recruit coactivators to promote transcription from target promoters. We hypothesize that variations in Response element architecture may influence both the association and dissociation of corepressors from DNA-bound thyroid Hormone receptors. Using a chimeric corepressor, we find that ligand alone does not fully relieve corepressor-mediated repression, particularly in the presence of thyroid Hormone receptor and its heterodimerization partner, the retinoid X receptor. Interestingly, the steroid receptor coactivator 1 together with ligand is able to mediate full release of corepression, but this relief is dependent upon the architecture of the Response element to which the nuclear receptor dimer-corepressor complex is bound. These studies suggest that other cellular factors in addition to ligand may be required for the release of corepressors from thyroid Hormone receptor dimers.
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5′-Flanking Sequences in Thyroid Hormone Response Element Half-sites Determine the Requirement of Retinoid X Receptor for Receptor-mediated Gene Expression
The Journal of biological chemistry, 1997Co-Authors: David P Olson, Ronald J KoenigAbstract:Thyroid Hormone receptors are ligand-inducible transcription factors that can potentially interact with thyroid Hormone Response elements as homodimers or heterodimers with the retinoid X receptor. It has generally been felt, however, that the heterodimer is responsible for induction of gene expression. We have demonstrated previously that the optimal thyroid Hormone receptor binding sequence is not the consensus hexamer half-site AGGTCA but is an octamer, TAAGGTCA. Based upon these findings, we hypothesize that thyroid Hormone Response elements composed of optimal half-sites (TAAGGTCA) will bind thyroid Hormone receptors readily and activate gene expression independently of the retinoid X receptor. In contrast, Response elements composed of suboptimal half-sites (e.g. GCAGGTCA) will require the retinoid X receptor to facilitate thyroid Hormone receptor-mediated gene expression. To test this hypothesis, we have reconstituted thyroid Hormone receptor-mediated gene expression in yeast. Our studies confirm the hypothesis that the retinoid X receptor is required for gene expression from Response elements composed of suboptimal half-sites, whereas thyroid Hormone receptors are sufficient to activate gene expression maximally from Response elements containing optimal half-sites. Furthermore, coexpression of steroid receptor coactivator-1 is required for ligand-dependent gene activation from single Response elements. Surprisingly, however, coexpression of the retinoid X receptor decreases the steroid receptor coactivator-1-dependent thyroid Hormone induction. Overall these data demonstrate that the architecture of the thyroid Hormone Response element dictates the nuclear receptor requirements for gene activation. The studies suggest that different coactivators may be required for gene activation depending upon the Response element architecture and the nature of the bound thyroid Hormone receptor complex (homo- versus heterodimer).
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5 flanking sequences in thyroid Hormone Response element half sites determine the requirement of retinoid x receptor for receptor mediated gene expression
Journal of Biological Chemistry, 1997Co-Authors: David P Olson, Ronald J KoenigAbstract:Thyroid Hormone receptors are ligand-inducible transcription factors that can potentially interact with thyroid Hormone Response elements as homodimers or heterodimers with the retinoid X receptor. It has generally been felt, however, that the heterodimer is responsible for induction of gene expression. We have demonstrated previously that the optimal thyroid Hormone receptor binding sequence is not the consensus hexamer half-site AGGTCA but is an octamer, TAAGGTCA. Based upon these findings, we hypothesize that thyroid Hormone Response elements composed of optimal half-sites (TAAGGTCA) will bind thyroid Hormone receptors readily and activate gene expression independently of the retinoid X receptor. In contrast, Response elements composed of suboptimal half-sites (e.g. GCAGGTCA) will require the retinoid X receptor to facilitate thyroid Hormone receptor-mediated gene expression. To test this hypothesis, we have reconstituted thyroid Hormone receptor-mediated gene expression in yeast. Our studies confirm the hypothesis that the retinoid X receptor is required for gene expression from Response elements composed of suboptimal half-sites, whereas thyroid Hormone receptors are sufficient to activate gene expression maximally from Response elements containing optimal half-sites. Furthermore, coexpression of steroid receptor coactivator-1 is required for ligand-dependent gene activation from single Response elements. Surprisingly, however, coexpression of the retinoid X receptor decreases the steroid receptor coactivator-1-dependent thyroid Hormone induction. Overall these data demonstrate that the architecture of the thyroid Hormone Response element dictates the nuclear receptor requirements for gene activation. The studies suggest that different coactivators may be required for gene activation depending upon the Response element architecture and the nature of the bound thyroid Hormone receptor complex (homo- versus heterodimer).
Ann Marie Zavacki - One of the best experts on this subject based on the ideXlab platform.
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Enhancement of thyroid Hormone receptor isoform specificity by insertion of a distant half-site into a thyroid Hormone Response element.
Endocrinology, 1996Co-Authors: Ann Marie Zavacki, C Y Zhang, John W. Harney, P R LarsenAbstract:The two isoforms of thyroid Hormone receptor (TR), alpha and beta, are highly homologous, except in the amino-terminal domain. Specific physiological roles for the receptor isoforms have not yet been defined. In transient transfection assays, TRalpha is twice as potent a thyroid Hormone (T3)-dependent transactivator as TRbeta on a number of thyroid Hormone Response elements (TREs). Using chimeras of TRalpha and -beta, we have determined that the higher transactivation by TRalpha requires the entire ligand-binding domain. The amino-terminal and DNA-binding domains of the two isoforms are interchangeable. These studies were facilitated by the use of a synthetic TRE composed of a direct repeat separated by 4 bp which also included a third half-site 19 bp 3' to this on the opposite strand. In the presence of T3, this TRE confers a 5-fold higher Response to TRalpha than to TRbeta, but there is no difference in expression without T3. Functional studies indicate that all three half-sites are needed for the incre...
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enhancement of thyroid Hormone receptor isoform specificity by insertion of a distant half site into a thyroid Hormone Response element
Endocrinology, 1996Co-Authors: Ann Marie Zavacki, C Y Zhang, John W. Harney, P R LarsenAbstract:The two isoforms of thyroid Hormone receptor (TR), alpha and beta, are highly homologous, except in the amino-terminal domain. Specific physiological roles for the receptor isoforms have not yet been defined. In transient transfection assays, TRalpha is twice as potent a thyroid Hormone (T3)-dependent transactivator as TRbeta on a number of thyroid Hormone Response elements (TREs). Using chimeras of TRalpha and -beta, we have determined that the higher transactivation by TRalpha requires the entire ligand-binding domain. The amino-terminal and DNA-binding domains of the two isoforms are interchangeable. These studies were facilitated by the use of a synthetic TRE composed of a direct repeat separated by 4 bp which also included a third half-site 19 bp 3' to this on the opposite strand. In the presence of T3, this TRE confers a 5-fold higher Response to TRalpha than to TRbeta, but there is no difference in expression without T3. Functional studies indicate that all three half-sites are needed for the increased responsiveness to TRalpha, but gel shift analyses show no striking differences in the ratios of TRalpha to TRbeta binding compared to other wild-type TREs. These results suggest that important functional differences are present in the ligand-binding domain of TRalpha and -beta despite their high homology.
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A NOVEL RETINOID X RECEPTOR-INDEPENDENT THYROID Hormone Response ELEMENT IS PRESENT IN THE HUMAN TYPE 1 DEIODINASE GENE
Molecular and cellular biology, 1995Co-Authors: N Toyoda, Ann Marie Zavacki, John W. Harney, Ana Luiza Maia, P R LarsenAbstract:We identified two thyroid Hormone Response elements (TREs) in the 2.5-kb, 5'-flanking region of the human gene encoding type 1 iodothyronine deiodinase (hdio1), an enzyme which catalyses the activation of thyroxine to 3,5,3'-triiodothyronine (T3). Both TREs contribute equally to T3 induction of the homologous promoter in transient expression assays. The proximal TRE (TRE1), which is located at bp -100, has an unusual structure, a direct repeat of the octamer YYRGGTCA hexamer that is spaced by 10 bp. The pyrimidines in the -2 position relative to the core hexamer are both essential to function. In vitro binding studies of TRE1 showed no heterodimer formation with retinoid X receptor (RXR) beta or JEG nuclear extracts (containing RXR alpha) and bacterially expressed chicken T3 receptor alpha 1 (TR alpha) can occupy both half-sites although the 3' half-site is dominant. T3 causes dissociation of TR alpha from the 5' half-site but increases binding to the 3' half-site. Binding of a second TR to TRE1 is minimally cooperative; however, no cooperativity was noted for a functional mutant in which the half-sites are separated by 15 bp, implying that TRs bind as independent monomers. Nonetheless, T3 still causes TR dissociation from the DR+15, indicating that dissociation occurs independently of TR-TR contact and that rebinding of a T3-TR complex to the 3' half-site occurs because of its slightly higher affinity. A distal TRE (TRE2) is found at bp -700 and is a direct repeat of a PuGGTCA hexamer spaced by 4 bp. It has typical TR homodimer and TR-RXR heterodimer binding properties. The TRE1 of hdio1 is the first example of a naturally occurring TRE consisting of two relatively independent octamer sequences which do not require the RXR family of proteins for function.
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retinoid x receptor rxr differentially augments thyroid Hormone Response in cell lines as a function of the Response element and endogenous rxr content
Endocrinology, 1995Co-Authors: J H Hsu, Ann Marie Zavacki, John W. Harney, G A BrentAbstract:Retinoid-X receptor (RXR) forms heterodimers with thyroid Hormone receptor (TR) and significantly enhances binding to thyroid Hormone Response elements (TREs). Expression of RXR in a transient transfection assay augments the T3 Response, but the influences of the specific cell line and TRE used have not been systematically studied. We determined RXR alpha and -beta augmentation of the TR alpha-mediated T3 Response in transient transfection assays of COS, JEG, and mouse embryonic stem (ES) cell lines for a series of eight wild-type thyroid Hormone (T3) and retinoic acid Response elements (previously shown to bind TR). RXR augmented T3-induced expression in COS and ES cells (1.5- to 4-fold greater expression with added RXR compared to TR alone), but had minimal effect on augmentation of Response in JEG cells. For most elements studied there was a proportional augmentation of basal and T3-stimulated expression. TREs from rat GH and laminin-B1, however, had relatively higher levels of T3-induced expression as...
Cary N. Mariash - One of the best experts on this subject based on the ideXlab platform.
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human spot 14 glucose and thyroid Hormone Response characterization and thyroid Hormone Response element identification
Endocrinology, 2003Co-Authors: Mark C. Campbell, Grant W. Anderson, Cary N. MariashAbstract:Spot 14 is a 17-kDa protein expressed in lipogenic tissues and is postulated to play a role in thyroid Hormone stimulation of lipogenesis. To further our understanding of Spot 14 regulation in humans, our laboratory recently cloned the human Spot 14 gene. The gene is highly homologous to the rat Spot 14 ortholog and located on a chromosomal region implicated in human obesity. Because our understanding of Spot 14 transcriptional regulation is derived from rat promoter studies, we assessed the thyroid Hormone responsivity of the human Spot 14 promoter. These studies revealed a significantly greater thyroid Hormone Response for the human promoter, compared with the rat. Deletional studies of the human Spot 14 promoter reveal a 774-bp region at approximately position −2700, which is both necessary and sufficient for the thyroid Hormone Response. EMSAs with subfragments from this region identify a 146-bp DNA fragment capable of binding a TRβ1-retinoid X receptor heterodimer. Site-directed mutagenesis confirmed...
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Human spot 14 glucose and thyroid Hormone Response: characterization and thyroid Hormone Response element identification.
Endocrinology, 2003Co-Authors: Mark C. Campbell, Grant W. Anderson, Cary N. MariashAbstract:Spot 14 is a 17-kDa protein expressed in lipogenic tissues and is postulated to play a role in thyroid Hormone stimulation of lipogenesis. To further our understanding of Spot 14 regulation in humans, our laboratory recently cloned the human Spot 14 gene. The gene is highly homologous to the rat Spot 14 ortholog and located on a chromosomal region implicated in human obesity. Because our understanding of Spot 14 transcriptional regulation is derived from rat promoter studies, we assessed the thyroid Hormone responsivity of the human Spot 14 promoter. These studies revealed a significantly greater thyroid Hormone Response for the human promoter, compared with the rat. Deletional studies of the human Spot 14 promoter reveal a 774-bp region at approximately position -2700, which is both necessary and sufficient for the thyroid Hormone Response. EMSAs with subfragments from this region identify a 146-bp DNA fragment capable of binding a TRbeta1-retinoid X receptor heterodimer. Site-directed mutagenesis confirmed the identity of a candidate DR-4 thyroid Hormone Response element within this fragment that is similar, but not identical, to the two rat Spot 14 thyroid Hormone Response elements. We hypothesize that the difference in thyroid Hormone Response between the orthologous promoters may allow a selective advantage to each species based on their different nutritional and physiological niches.