Thyroid hormone receptor-alpha inhibits retinoic acid-responsive gene expression and modulates retinoic acid-stimulated neural differentiation in mouse embryonic stem cells.

Lee, Ling-Ru; Mortensen, Richard M.; Larson, Cecilia A.; Brent, Gregory A.

doi:10.1210/mend.8.6.7935490

Cited by 12 publications

(8 citation statements)

References 13 publications

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“…We have previously reported on differentiation of mouse ES cells into neurons using T 3 and RA (43,44). ES cells were differentiated by treatment for 5 d with T 3 , RA, or T 3 /RA.…”

Section: Endogenous Regulation Of Camkiv In Mouse Es Cellsmentioning

confidence: 99%

“…2). ES cells contain endogenous TR and RAR sufficient for a T 3 and RA response (43). T 3 treatment induced the Ϫ1060 CaMKIV-chloramphenicol acetyltransferase (CAT) construct about 3-fold.…”

Section: T 3 and Ra Induction Of Camkiv 5-flanking Region In Es Cellsmentioning

confidence: 99%

“…ES cell neural differentiation was modified from a previously described technique (43,44). ES cells were plated without feeder cells or gelatin coating to form embryoid bodies.…”

Section: Cell Culture and Differentiation Conditionsmentioning

confidence: 99%

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A Complex Deoxyribonucleic Acid Response Element in the Rat Ca2+/Calmodulin-Dependent Protein Kinase IV Gene 5′-Flanking Region Mediates Thyroid Hormone Induction and Chicken Ovalbumin Upstream Promoter Transcription Factor 1 Repression

Liu

Brent

2002

Molecular Endocrinology

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Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) is regulated by T(3) in a time- and concentration-dependent manner in the developing rat brain and plays an important role in neuronal-specific gene regulation. T(3) treatment, but not retinoic acid (RA), stimulated endogenous CaMKIV mRNA 5-fold in mouse embryonic stem (ES) cells differentiated into neurons. We localized a region -750 to -700 in the CaMKIV gene 5'-flanking region that conferred T(3) responsiveness and bound thyroid hormone receptor (TR), retinoic acid receptor (RAR), and chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1). T(3) and RA treatment stimulated the CaMKIV hormone response element. Cotransfection of a COUP-TF1 expression vector repressed the T(3) response and augmented the RA response. Mutational analysis identified three half-sites arranged in a direct repeat (AB) and overlapping inverted repeat (BC), required for functional induction and receptor binding. TR and RAR bound predominantly to the BC portion of the element and COUP-TF1 to the AB region, with a close correlation of binding and functional studies. COUP-TF1 binding did not influence TR/retinoid X receptor binding but modestly augmented RAR/retinoid X receptor binding. A single element confers T(3) and COUP-TF1 regulation of CaMKIV expression.

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“…We have previously reported on differentiation of mouse ES cells into neurons using T 3 and RA (43,44). ES cells were differentiated by treatment for 5 d with T 3 , RA, or T 3 /RA.…”

Section: Endogenous Regulation Of Camkiv In Mouse Es Cellsmentioning

confidence: 99%

Section: T 3 and Ra Induction Of Camkiv 5-flanking Region In Es Cellsmentioning

confidence: 99%

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A Complex Deoxyribonucleic Acid Response Element in the Rat Ca2+/Calmodulin-Dependent Protein Kinase IV Gene 5′-Flanking Region Mediates Thyroid Hormone Induction and Chicken Ovalbumin Upstream Promoter Transcription Factor 1 Repression

Liu

Brent

2002

Molecular Endocrinology

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“…The observations showing that the injection of TRct! in frog oocytes, before the presence of thyroid gland, protects injected embryos from retinole acid teratogenesis (8) and that the unligated TRa, inhibits the retinoic acid-stimulated differentiation of mouse embryonic stem cells in vitro (9) are consistent with such a possibility. This also indicates that the presence or the absence of other members of the nuclear receptor family in a specific cell type could interfere with the ability of TRs to form heterodimers and thus with their transcriptional activity.…”

mentioning

confidence: 71%

Thyroid hormone receptors are necessary but not sufficient for transcription

Puymirat¹

1996

European Journal of Endocrinology

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Lopez-Barahona et al. report in this issue the differential regulation of beta-1 adrenergic receptor (\g=b\1-AR)gene expression by thyroid hormones in myocytes and C6 glioma cells. They found that triiodothyronine (T3) regulates \g=b\1-AR in myocytes but not in C6 glioma cells. Because the T3 binding capacity and the levels of thyroid hormone receptor (TR) mRNAs are low in C6 glioma cells, they have overexpressed TR\g=a\1 in order to determine whether increased levels of TRs would increase the sensitivity of these cells to T3. Although TR\g=a\1 was functional in transfected cells, no effect of T3 was observed on \g=b\1-ARgene expression. These data suggest cell-specific regulation of gene expression by thyroid hormones and raise the important question about the mechanisms that underlie the cellular specificity in the action of thyroid hormones.It is generally accepted that the primary actions of thyroid hormones are mediated via an interaction with specific TRs. The binding of thyroid hormones to their receptors regulates the expression of a limited number of mRNAs encoding for a set of proteins. Two genes that encode TRs have been identified and classified in a-and /3-subtypes (for a review see Ref. 1). In the rat, three T3 binding proteins (ai: ßi, ß2) and two variants of the aj protein (a2 variants) that do not bind T3 were identified. Furthermore, opposite-strand transcription of the gene is responsible for the formation of a non-T3 binding protein called Rev-ErbAa.These different TR isoforms have a tissue-specific expression, suggesting isoform-specific functions that depend on cell type. The recent observations showing that TR/3j but not TRaj regulates PCP-2 gene expres¬ sion in transient transfection experiments (2), and that overexpression of TR/îj but not that of TRctj induces differentiation of a neuroblastoma cell line (neuro-2a) (3), are consistent with this possibility. Both TRct; and TR/3] are expressed by myocytes whereas only TRai is expressed by C6 glioma cells. It is therefore possible that the regulation of/Jj-AR gene expression by T3 might be mediated via TRß\. On the other hand, C6 glioma cells also express the a2 variants that do not bind T3 and are expressed at more than ten-fold the levels of TRa^a nd TR/3], demonstrating a dominant negative effect (4). From these data, it was postulated that the «2 proteins might interfere with TR functions, thereby rendering the cell less sensitive to T3. In their report, LopezBarahona et al. show that the lack of responsiveness of /3i-AR gene to T3 in C6 cells is not due to the high level of expression of the a2 variants. Indeed, the al variants are expressed at least 10-to 20-fold more than those of TR«! and TR/?! in several T3-responsive cells, including myocytes and fetal brain cells.Alternatively, the data reported by Lopez-Barahona et al. may suggest that the presence of TRs is necessary but not sufficient for the regulation of gene expression by thyroid hormones. Consistent with this, T3 regulates TKßi gene expression in glial but not in neuronal ...

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“…It is possible that TR␣1 may have a ligandindependent function in early brain development (145). It is possible that TR␣1 may have a ligandindependent function in early brain development (145).…”

Section: Theories and Speculationsmentioning

confidence: 99%