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• W2023999213 abstract "Thyroid hormone (3,5,3′-triiodothyronine; T3) is essential for normal development of the vertebrate brain, influencing diverse processes such as neuronal migration, myelin formation, axonal maturation, and dendritic outgrowth. We have identified basic transcription element-binding protein (BTEB), a small GC box-binding protein, as a T3-regulated gene in developing rat brain. BTEB mRNA levels in cerebral cortex exhibit developmental regulation and thyroid hormone dependence. T3 regulation of BTEB mRNA is neural cell-specific, being up-regulated in primary cultures of embryonic neurons (E16) and in neonatal astrocytes (P2), but not in neonatal oligodendrocytes (P2). T3 rapidly up-regulated BTEB mRNA in neuro-2a cells engineered to express thyroid hormone receptor (TR) β1 but not in cells expressing TRα1, suggesting that the regulation of this gene is specific to the TRβ1 isoform. Several lines of evidence support a transcriptional action of T3 on BTEB gene expression. Overexpression of BTEB in Neuro-2a cells dramatically increased the number and length of neurites in a dose-dependent manner suggesting a role for this transcription factor in neuronal process formation. However, other T3-dependent changes were not altered;i.e. overexpression of BTEB had no effect on the rate of cell proliferation nor on the expression of acetylcholinesterase activity. Thyroid hormone (3,5,3′-triiodothyronine; T3) is essential for normal development of the vertebrate brain, influencing diverse processes such as neuronal migration, myelin formation, axonal maturation, and dendritic outgrowth. We have identified basic transcription element-binding protein (BTEB), a small GC box-binding protein, as a T3-regulated gene in developing rat brain. BTEB mRNA levels in cerebral cortex exhibit developmental regulation and thyroid hormone dependence. T3 regulation of BTEB mRNA is neural cell-specific, being up-regulated in primary cultures of embryonic neurons (E16) and in neonatal astrocytes (P2), but not in neonatal oligodendrocytes (P2). T3 rapidly up-regulated BTEB mRNA in neuro-2a cells engineered to express thyroid hormone receptor (TR) β1 but not in cells expressing TRα1, suggesting that the regulation of this gene is specific to the TRβ1 isoform. Several lines of evidence support a transcriptional action of T3 on BTEB gene expression. Overexpression of BTEB in Neuro-2a cells dramatically increased the number and length of neurites in a dose-dependent manner suggesting a role for this transcription factor in neuronal process formation. However, other T3-dependent changes were not altered;i.e. overexpression of BTEB had no effect on the rate of cell proliferation nor on the expression of acetylcholinesterase activity. 3,5,3′-triiodothyronine central nervous system thyroid hormone receptor basic transcription element-binding protein propylthiouracil acetylcholinesterase 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Thyroid hormone (3,5,3′-triiodothyronine; T3)1 is essential for normal development of the vertebrate central nervous system (CNS). Thyroid hormone deficiency during the period of active neurogenesis (up to 6 months post-partum in humans) results in irreversible mental retardation (i.e. cretinism; Refs. 1Legrand J. J. Physiol. (Paris). 1983; 78: 603-652Google Scholar and 2Porterfield S.P. Hendrich C.E. Endocr. Rev. 1993; 14: 94-106PubMed Google Scholar). The hormone influences diverse processes in the developing brain including neuronal maturation, neurite outgrowth, synapse formation, and myelination (2Porterfield S.P. Hendrich C.E. Endocr. Rev. 1993; 14: 94-106PubMed Google Scholar). Severe morphological alterations in the brains of hypothyroid rats are due to impairment of neuronal migration and hypoplasia of neuronal processes which together lead to a reduction in the number of neural circuits (1Legrand J. J. Physiol. (Paris). 1983; 78: 603-652Google Scholar, 2Porterfield S.P. Hendrich C.E. Endocr. Rev. 1993; 14: 94-106PubMed Google Scholar, 3Dussault J.H. Ruel J. Annu. Rev. Physiol. 1987; 49: 321-334Crossref PubMed Google Scholar).Relatively little is known of the molecular mechanisms of T3 action on the developing brain. The actions of T3 are mediated by ligand-dependent transcription factors (4Tsai M.J. O'Malley B.W. Annu. Rev. Biochem. 1994; 63: 451-486Crossref PubMed Scopus (2678) Google Scholar, 5Mangelsdorf D.J. Thummel C. Beato M. Herrlich P. Schutz G. Umesono K. Blumberg B. Kastner P. Mark M. Chambon P. Evans R.M. Cell. 1995; 83: 835-840Abstract Full Text PDF PubMed Scopus (6027) Google Scholar). Three functional thyroid hormone receptors (TRα1, TRβ1, and TRβ2) encoded by two genes (α and β) have been identified (6Forrest D. Cancer Biol. 1994; 5: 167-176PubMed Google Scholar). In the rat brain TRα1 expression is detected by embryonic day 14 and remains the major TR isoform expressed before postnatal day 7, while the TRβ1 becomes the predominant TR isoform after the second week of life (7Puymirat J. Prog. Neurobiol. 1992; 39: 281-294Crossref PubMed Scopus (78) Google Scholar). The differential expression of the TR isoforms suggests developmental and brain region-specific functions for these receptors (6Forrest D. Cancer Biol. 1994; 5: 167-176PubMed Google Scholar, 7Puymirat J. Prog. Neurobiol. 1992; 39: 281-294Crossref PubMed Scopus (78) Google Scholar, 8Lebel J.M. L'Herault S. Dussault J.H. Puymirat J. Glia. 1993; 9: 105-112Crossref PubMed Scopus (43) Google Scholar, 9Lebel J.M. Dussault J.H. Puymirat J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2644-2648Crossref PubMed Scopus (82) Google Scholar).Differential screening experiments have identified several T3-regulated genes in the rodent CNS (10Munoz A. Rodriguez-Pena A. Perez-Castillo A. Ferreiro B. Sutcliffe J.G. Bernal J. Mol. Endocrinol. 1991; 5: 273-280Crossref PubMed Scopus (136) Google Scholar, 11Iglesias T. Caubin J. Zaballos A. Bernal J. Munoz A. Biochem. Biophys. Res. Commun. 1995; 210: 995-1000Crossref PubMed Scopus (54) Google Scholar, 12Vega-Nunez E. Menendez-Hurtado A. Garesse R. Santos A. Perez-Castillo A. J. Clin. Invest. 1995; 96: 893-899Crossref PubMed Scopus (57) Google Scholar, 13Iglesias T. Caubin J. Stunnenberg H.G. Zaballos A. Bernal J. Munoz A. EMBO J. 1996; 15: 4307-4316Crossref PubMed Scopus (74) Google Scholar, 14Thompson C.C. J. Neurosci. 1996; 16: 7832-7840Crossref PubMed Google Scholar); but, roles for the protein products of these genes in T3 action on the brain have not been established. Using a gene expression screen (15Wang Z. Brown D.D. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 11505-11509Crossref PubMed Scopus (297) Google Scholar) we recently isolated a large set of early T3-responsive genes from the Xenopus tadpole CNS, several of which encode transcriptional regulatory proteins (16Denver R.J. Pavgi S. Shi Y.-B. J. Biol. Chem. 1997; 272: 8179-8188Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). We identified one of these genes as the Xenopus homolog of the mammalian basic transcription element-binding protein (BTEB), a small GC box-binding protein capable of activating or repressing the transcription of genes with GC-box sequences in their promoter (17Imataka H. Sogawa K. Yasumoto K. Kikuchi Y. Sasano K. Kobayashi A. Hayami M. Fujii-Kuriyama Y. EMBO J. 1992; 11: 3663-3671Crossref PubMed Scopus (307) Google Scholar, 18Brown D.D. Wang Z. Furlow J.D. Kanamori A. Schwartzman R.A. Remo B.F. Pinder A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 1924-1929Crossref PubMed Scopus (218) Google Scholar). BTEB has significant sequence similarity to the Sp family of transcription factors, primarily in the zinc finger region (DNA-binding domain). But beyond the DNA-binding domain the two proteins share little similarity. For example, rat Sp1 is a 788-amino acid protein while rat BTEB is only 244 amino acids in length. Interestingly, while BTEB mRNA is ubiquitously expressed in the rat, the mRNA appears to be translated only in the brain (19Imataka H. Nakayama K. Yasumoto K. Mizuno A. Fujii-Kuriyama Y. Hayami M. J. Biol. Chem. 1994; 269: 20668-20673Abstract Full Text PDF PubMed Google Scholar).Using a cross-species hybridization approach we identified BTEB as a T3-regulated gene in developing rat brain. The objectives of the present study were to analyze the developmental and T3-dependent expression of BTEB in rat brain, and to test for a role for this transcription factor in T3-dependent effects on the developing brain.DISCUSSIONWe have identified the small GC box-binding transcription factor BTEB as a T3-regulated gene in the developing rodent CNS. The expression of BTEB mRNA in the developing rat brain depends on thyroid status; the induction of hypothyroidism in neonatal pups resulted in reduced expression that was restored by T3replacement therapy. Furthermore, the gene is developmentally regulated, exhibiting a distinct elevation in expression that parallels developmentally-dependent increases in plasma T3 levels (2Porterfield S.P. Hendrich C.E. Endocr. Rev. 1993; 14: 94-106PubMed Google Scholar). Similar to other T3 responsive genes in the developing CNS, T3 regulation of BTEB gene expression disappears in the adult (Ref. 37Strait K.A. Zou L. Oppenheimer J.H. Mol. Endocrinol. 1992; 6: 1874-1880PubMed Google Scholar; see Fig. 2).BTEB is the first T3-responsive gene to be identified that is differentially regulated by T3 in specific neural cell types. We showed that BTEB mRNA expression is up-regulated by T3 in primary neurons and astrocytes derived from embryonic and neonatal rat brain, respectively, but not in oligodendrocytes. The effect of T3 on BTEB mRNA levels in primary neurons is unlikely to be due to contaminating astrocytes (which represent ∼15% of the cell population) since the degree of BTEB mRNA induction in neuronal cultures is much greater than that observed in the astrocyte cultures (6.5 versus 1.3-fold). Because most of the neurons cease division after 8 days in vitro , our results indicate that the effect of T3 on BTEB gene expression occurs in post-mitotic neurons. This result is consistent with the up-regulation of BTEB mRNA by T3 observed in the brain of the P22 rat (see Fig. 1). Similarly, we have found that the effect of T3 on BTEB mRNA levels in N-2a[TRβ1] cells is absent during the first 48 h of culture and is not expressed until the cells are confluent. This suggests that the cells must cease division before BTEB can be up-regulated by T3. We have not yet determined whether neurons and astrocytes express BTEB and are responsive to T3 in vivo ; however, it is noteworthy that our previous work has shown that these primary neurons express their program of differentiation similar to that observedin vivo (20Puymirat J. L'Herault S. Dussault J.H. Dev. Brain Res. 1992; 69: 173-177Crossref PubMed Scopus (18) Google Scholar, 32Puymirat J. Faivre-Bauman A. Neurosci. Lett. 1986; 68: 299-304Crossref PubMed Scopus (24) Google Scholar).Our findings demonstrate the utility of using a cross-species hybridization approach to identify novel hormone-regulated genes in the developing rodent brain. Recent attempts to isolate T3-regulated genes in neonatal rodent brain by differential screening procedures have met with limited success. These studies have lead to the identification of several mitochondrial genes (12 S and 16 S rRNAs, cytochrome c oxidase subunit III and NADH dehydrogenase subunit 3; Refs. 11Iglesias T. Caubin J. Zaballos A. Bernal J. Munoz A. Biochem. Biophys. Res. Commun. 1995; 210: 995-1000Crossref PubMed Scopus (54) Google Scholar and 12Vega-Nunez E. Menendez-Hurtado A. Garesse R. Santos A. Perez-Castillo A. J. Clin. Invest. 1995; 96: 893-899Crossref PubMed Scopus (57) Google Scholar), a tubulin and NCAM (13Iglesias T. Caubin J. Stunnenberg H.G. Zaballos A. Bernal J. Munoz A. EMBO J. 1996; 15: 4307-4316Crossref PubMed Scopus (74) Google Scholar), a novel synaptogamin-related protein (involved with regulating neurotransmitter release) and a zinc finger protein related to the product of a recently identify mouse gene, hairless (14Thompson C.C. J. Neurosci. 1996; 16: 7832-7840Crossref PubMed Google Scholar, 38Thompson C.C. Bottcher M.C. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8527-8532Crossref PubMed Scopus (124) Google Scholar). Given the dramatic and pleiotropic effects of T3 on CNS development, this set of genes likely represents only a small fraction of the total number of genes controlled by the hormone. Also, given that thyroid and steroid hormones bring about developmental changes by activating gene regulation programs, it is surprising that so few transcriptional regulatory proteins have been isolated from rodent brain as T3-responsive genes. We previously isolated by subtractive hybridization 34 cDNAs that correspond to T3-regulated genes in the Xenopus tadpole CNS (16Denver R.J. Pavgi S. Shi Y.-B. J. Biol. Chem. 1997; 272: 8179-8188Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Several of these genes are transcriptional regulatory proteins, and we hypothesized that similar sets of genes would be regulated by the hormone in mammal brain. BTEB is the first such gene that we have analyzed and found to be similarly regulated in frog and rodent brain. Our success raises the possibility that other rat homologs of frog genes isolated by our gene expression screen will also be found to be regulated by T3in the developing mammal brain.BTEB Gene Regulation May Be Specific to the TRβ1 IsoformBecause TRα1 and TRβ1 are differentially expressed in the developing brain we hypothesized that each TR isoform might regulate distinct sets of genes in different brain regions. Lebel and colleagues (9Lebel J.M. Dussault J.H. Puymirat J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2644-2648Crossref PubMed Scopus (82) Google Scholar) developed neuronal cell lines (Neuro-2a cells; derived from a mouse neuroblastoma) that overexpress either the TRα1 or TRβ1 isoform (N-2a[TRα1] or N-2a[TRβ1]). Our results using these two cell lines suggest that BTEB gene regulation is specific to the TRβ1 isoform. These two cell lines express similar levels of T3 binding activity (∼7-fold over the parental cell line). Furthermore, the TRα1 expression plasmid produces a transcriptionally active receptor in a transient transfection assay using a luciferase reporter gene construct under control of a thyroid hormone response element (9Lebel J.M. Dussault J.H. Puymirat J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2644-2648Crossref PubMed Scopus (82) Google Scholar). It is noteworthy that when constructing the overexpressing cell lines, Lebel and colleagues screened 20 TRα1-expressing clones and none were responsive to T3 in terms of its antiproliferative and differentiative effects. Conversely, the majority of TRβ1-expressing clones were responsive to T3. Taken together, our results support the view that BTEB is regulated by T3 through a specific interaction with the TRβ1 in neural cells. Whether such differential gene regulation by TR isoforms occurs in the developing brain has not yet been determined. However, correlative evidence suggests that BTEB may be regulated by T3 through an interaction with TRβ1 in the developing brain. For example, the expression of BTEB mRNA and its regulation by T3 correlates more closely with the appearance of TRβ1 than it does with TRα1 in primary neuronal cultures (20Puymirat J. L'Herault S. Dussault J.H. Dev. Brain Res. 1992; 69: 173-177Crossref PubMed Scopus (18) Google Scholar) and in the developing rat brain (7Puymirat J. Prog. Neurobiol. 1992; 39: 281-294Crossref PubMed Scopus (78) Google Scholar).Transcriptional Regulation of BTEB Gene Expression by Thyroid HormoneThe rapid kinetics of T3 up-regulation of BTEB mRNA in N-2a[TRβ1] cells (see Fig. 4) suggested that T3 might directly regulate BTEB gene transcription. Our finding that the up-regulation of BTEB mRNA by T3occurs in the presence of the protein synthesis inhibitor cycloheximide provides further support for this hypothesis. The effect of T3 is probably not due to the stabilization of the mRNA since treatment with actinomycin D abolished the T3 effect on the level of BTEB mRNA. In addition, nuclear run-on analysis experiments confirm that T3 alters the rate of transcription of the BTEB gene (Fig. 6). Taken together, these results provide strong support for a direct transcriptional action of T3 on BTEB gene expression.Functional Consequences of BTEB Gene ExpressionThe expression of the BTEB gene in the developing rat brain coincides with the neonatal rise in TRβ1 and with the neonatal surge in the level of serum T3, suggesting that BTEB could mediate some of the postnatal effects of T3 on neural cell differentiation. Although there is evidence for a role for thyroid hormones in the control of the duration of the proliferative phase of neuroblasts and oligodendrocyte progenitors, our results argue against a role for BTEB in these actions. T3 regulates BTEB gene expression in post-mitotic cultured neurons and, BTEB is expressed essentially postnatally in the developing cerebral hemispheres during a period where most neuronal cells have ceased mitosis. It is also unlikely that BTEB is involved in the effect of T3 on the control of the proliferative phase of oligodendrocyte progenitors (O-2A) since these cells do not express TRβ1 (39Baas D. Bourbeau D. Sarlieve L.L. Dussault J.H. Puymirat J. Glia. 1997; 19: 324-332Crossref PubMed Scopus (150) Google Scholar).It is well established that the absence of thyroid hormone during the neonatal/postnatal period causes profound alterations in CNS development, including deficiency in myelination, neurite outgrowth, and the development of specific neuronal functions. It is unlikely that BTEB is involved with T3 action on myelination since the gene does not appear to be regulated by T3 in oligodendrocytes, at least not in vitro . A major effect of T3 on primary cultured neurons is on neurite outgrowth (21Garza R. Dussault J.H. Puymirat J. Dev. Brain Res. 1988; 43: 287-298Crossref Scopus (28) Google Scholar); similar effects of the hormone are seen in N-2a[TRβ1] cells (9Lebel J.M. Dussault J.H. Puymirat J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2644-2648Crossref PubMed Scopus (82) Google Scholar). In the present study, in addition to increasing the number of neurites (as reported by Lebel et al. (9Lebel J.M. Dussault J.H. Puymirat J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2644-2648Crossref PubMed Scopus (82) Google Scholar)) we found that T3 treatment of N-2a[TRβ1] cells also increased neurite length. This difference is most likely due to the different incubation times in the two studies (48 h exposure to T3 in the study by Lebel et al. (9Lebel J.M. Dussault J.H. Puymirat J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2644-2648Crossref PubMed Scopus (82) Google Scholar) versus 5 day exposure to T3 in the present study).Our findings support a role for BTEB in mediating some of the postnatal effects of thyroid hormone. Here we show that expression of BTEB induces neurite outgrowth in N-2a cells. This effect was observed after 5 days in culture when most cells are confluent, suggesting that N-2a cells must cease division, probably by contact inhibition, before the up-regulation of BTEB can exert its effects on neurite outgrowth. It is noteworthy that the level of BTEB mRNA expression in clone number 10 (3-fold) is comparable to the level of T3-induced expression of this gene in both primary neurons (Fig. 3) and N-2a[TRβ] cells (Fig. 4). Furthermore, the number and length of neurites observed with N-2a[BTEB] clone number 10 was comparable to that observed in N-2a[TRβ1] cells treated with T3 for 5 days (see Table II; Fig. 7). These observations argue against the generation of a neomorphic phenotype as a result of overexpression of this transcription factor. Because our results with BTEB overexpression were obtained in a stably transfected neuroblastoma cell line, at present we can only speculate on the role that BTEB plays in vivo in the developing brain. However, taken together, our findings suggest that BTEB could be a critical component of the signaling pathway induced by the hormone in the developing brain; studies are underway to test this hypothesis in primary neurons. Furthermore, the parallel between the effect of T3 on neurite outgrowth and the associated elevation of BTEB mRNA in primary neuronal cultures is consistent with this hypothesis (21Garza R. Dussault J.H. Puymirat J. Dev. Brain Res. 1988; 43: 287-298Crossref Scopus (28) Google Scholar).The transcriptional regulation of BTEB gene expression by T3 suggests that up-regulation of this transcription factor is one of the earliest events (following TR activation) in T3-induced neurite outgrowth. The absence of an effect of BTEB overexpression on AchE activity in N-2a cells indicates that different transcriptional regulatory pathways mediate the action of T3 on neurite outgrowth and the induction AchE activity. These findings illustrate the complexity of the molecular mechanisms that underly the action of the hormone in specific neural cell types. The earliest observed effect of T3 in N-2a[TRβ] cells is to block, by an unknown mechanism, cellular proliferation (9Lebel J.M. Dussault J.H. Puymirat J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2644-2648Crossref PubMed Scopus (82) Google Scholar). AchE activity is then stimulated and this involves the activation of a serine/threonine protein kinase pathway (33Puymirat J. Etongue-Mayer P. Dussault J.H. J. Biol. Chem. 1995; 270: 30651-30656Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). The cessation of cellular proliferation is followed by an increase in neurite outgrowth, most probably through activation of BTEB gene expression. Our results indicate that T3 can produce a variety of cell-type and temporally-specific effects through an interaction with the same thyroid hormone receptor. Our findings provide a first step toward understanding the complex gene expression changes induced by the hormone in the developing brain. Thyroid hormone (3,5,3′-triiodothyronine; T3)1 is essential for normal development of the vertebrate central nervous system (CNS). Thyroid hormone deficiency during the period of active neurogenesis (up to 6 months post-partum in humans) results in irreversible mental retardation (i.e. cretinism; Refs. 1Legrand J. J. Physiol. (Paris). 1983; 78: 603-652Google Scholar and 2Porterfield S.P. Hendrich C.E. Endocr. Rev. 1993; 14: 94-106PubMed Google Scholar). The hormone influences diverse processes in the developing brain including neuronal maturation, neurite outgrowth, synapse formation, and myelination (2Porterfield S.P. Hendrich C.E. Endocr. Rev. 1993; 14: 94-106PubMed Google Scholar). Severe morphological alterations in the brains of hypothyroid rats are due to impairment of neuronal migration and hypoplasia of neuronal processes which together lead to a reduction in the number of neural circuits (1Legrand J. J. Physiol. (Paris). 1983; 78: 603-652Google Scholar, 2Porterfield S.P. Hendrich C.E. Endocr. Rev. 1993; 14: 94-106PubMed Google Scholar, 3Dussault J.H. Ruel J. Annu. Rev. Physiol. 1987; 49: 321-334Crossref PubMed Google Scholar). Relatively little is known of the molecular mechanisms of T3 action on the developing brain. The actions of T3 are mediated by ligand-dependent transcription factors (4Tsai M.J. O'Malley B.W. Annu. Rev. Biochem. 1994; 63: 451-486Crossref PubMed Scopus (2678) Google Scholar, 5Mangelsdorf D.J. Thummel C. Beato M. Herrlich P. Schutz G. Umesono K. Blumberg B. Kastner P. Mark M. Chambon P. Evans R.M. Cell. 1995; 83: 835-840Abstract Full Text PDF PubMed Scopus (6027) Google Scholar). Three functional thyroid hormone receptors (TRα1, TRβ1, and TRβ2) encoded by two genes (α and β) have been identified (6Forrest D. Cancer Biol. 1994; 5: 167-176PubMed Google Scholar). In the rat brain TRα1 expression is detected by embryonic day 14 and remains the major TR isoform expressed before postnatal day 7, while the TRβ1 becomes the predominant TR isoform after the second week of life (7Puymirat J. Prog. Neurobiol. 1992; 39: 281-294Crossref PubMed Scopus (78) Google Scholar). The differential expression of the TR isoforms suggests developmental and brain region-specific functions for these receptors (6Forrest D. Cancer Biol. 1994; 5: 167-176PubMed Google Scholar, 7Puymirat J. Prog. Neurobiol. 1992; 39: 281-294Crossref PubMed Scopus (78) Google Scholar, 8Lebel J.M. L'Herault S. Dussault J.H. Puymirat J. Glia. 1993; 9: 105-112Crossref PubMed Scopus (43) Google Scholar, 9Lebel J.M. Dussault J.H. Puymirat J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2644-2648Crossref PubMed Scopus (82) Google Scholar). Differential screening experiments have identified several T3-regulated genes in the rodent CNS (10Munoz A. Rodriguez-Pena A. Perez-Castillo A. Ferreiro B. Sutcliffe J.G. Bernal J. Mol. Endocrinol. 1991; 5: 273-280Crossref PubMed Scopus (136) Google Scholar, 11Iglesias T. Caubin J. Zaballos A. Bernal J. Munoz A. Biochem. Biophys. Res. Commun. 1995; 210: 995-1000Crossref PubMed Scopus (54) Google Scholar, 12Vega-Nunez E. Menendez-Hurtado A. Garesse R. Santos A. Perez-Castillo A. J. Clin. Invest. 1995; 96: 893-899Crossref PubMed Scopus (57) Google Scholar, 13Iglesias T. Caubin J. Stunnenberg H.G. Zaballos A. Bernal J. Munoz A. EMBO J. 1996; 15: 4307-4316Crossref PubMed Scopus (74) Google Scholar, 14Thompson C.C. J. Neurosci. 1996; 16: 7832-7840Crossref PubMed Google Scholar); but, roles for the protein products of these genes in T3 action on the brain have not been established. Using a gene expression screen (15Wang Z. Brown D.D. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 11505-11509Crossref PubMed Scopus (297) Google Scholar) we recently isolated a large set of early T3-responsive genes from the Xenopus tadpole CNS, several of which encode transcriptional regulatory proteins (16Denver R.J. Pavgi S. Shi Y.-B. J. Biol. Chem. 1997; 272: 8179-8188Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). We identified one of these genes as the Xenopus homolog of the mammalian basic transcription element-binding protein (BTEB), a small GC box-binding protein capable of activating or repressing the transcription of genes with GC-box sequences in their promoter (17Imataka H. Sogawa K. Yasumoto K. Kikuchi Y. Sasano K. Kobayashi A. Hayami M. Fujii-Kuriyama Y. EMBO J. 1992; 11: 3663-3671Crossref PubMed Scopus (307) Google Scholar, 18Brown D.D. Wang Z. Furlow J.D. Kanamori A. Schwartzman R.A. Remo B.F. Pinder A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 1924-1929Crossref PubMed Scopus (218) Google Scholar). BTEB has significant sequence similarity to the Sp family of transcription factors, primarily in the zinc finger region (DNA-binding domain). But beyond the DNA-binding domain the two proteins share little similarity. For example, rat Sp1 is a 788-amino acid protein while rat BTEB is only 244 amino acids in length. Interestingly, while BTEB mRNA is ubiquitously expressed in the rat, the mRNA appears to be translated only in the brain (19Imataka H. Nakayama K. Yasumoto K. Mizuno A. Fujii-Kuriyama Y. Hayami M. J. Biol. Chem. 1994; 269: 20668-20673Abstract Full Text PDF PubMed Google Scholar). Using a cross-species hybridization approach we identified BTEB as a T3-regulated gene in developing rat brain. The objectives of the present study were to analyze the developmental and T3-dependent expression of BTEB in rat brain, and to test for a role for this transcription factor in T3-dependent effects on the developing brain. DISCUSSIONWe have identified the small GC box-binding transcription factor BTEB as a T3-regulated gene in the developing rodent CNS. The expression of BTEB mRNA in the developing rat brain depends on thyroid status; the induction of hypothyroidism in neonatal pups resulted in reduced expression that was restored by T3replacement therapy. Furthermore, the gene is developmentally regulated, exhibiting a distinct elevation in expression that parallels developmentally-dependent increases in plasma T3 levels (2Porterfield S.P. Hendrich C.E. Endocr. Rev. 1993; 14: 94-106PubMed Google Scholar). Similar to other T3 responsive genes in the developing CNS, T3 regulation of BTEB gene expression disappears in the adult (Ref. 37Strait K.A. Zou L. Oppenheimer J.H. Mol. Endocrinol. 1992; 6: 1874-1880PubMed Google Scholar; see Fig. 2).BTEB is the first T3-responsive gene to be identified that is differentially regulated by T3 in specific neural cell types. We showed that BTEB mRNA expression is up-regulated by T3 in primary neurons and astrocytes derived from embryonic and neonatal rat brain, respectively, but not in oligodendrocytes. The effect of T3 on BTEB mRNA levels in primary neurons is unlikely to be due to contaminating astrocytes (which represent ∼15% of the cell population) since the degree of BTEB mRNA induction in neuronal cultures is much greater than that observed in the astrocyte cultures (6.5 versus 1.3-fold). Because most of the neurons cease division after 8 days in vitro , our results indicate that the effect of T3 on BTEB gene expression occurs in post-mitotic neurons. This result is consistent with the up-regulation of BTEB mRNA by T3 observed in the brain of the P22 rat (see Fig. 1). Similarly, we have found that the effect of T3 on BTEB mRNA levels in N-2a[TRβ1] cells is absent during the first 48 h of culture and is not expressed until the cells are confluent. This suggests that the cells must cease division before BTEB can be up-regulated by T3. We have not yet determined whether neurons and astrocytes express BTEB and are responsive to T3 in vivo ; however, it is noteworthy that our previous work has shown that these primary neurons express their program of differentiation similar to that observedin vivo (20Puymirat J. L'Herault S. Dussault J.H. Dev. Brain Res. 1992; 69: 173-177Crossref PubMed Scopus (18) Goo" @default.
• W2023999213 created "2016-06-24" @default.
• W2023999213 creator A5021794602 @default.
• W2023999213 creator A5026971661 @default.
• W2023999213 creator A5034759974 @default.
• W2023999213 creator A5036673188 @default.
• W2023999213 creator A5049582015 @default.
• W2023999213 creator A5069642074 @default.
• W2023999213 date "1999-08-01" @default.
• W2023999213 modified "2023-10-16" @default.
• W2023999213 title "Basic Transcription Element-binding Protein (BTEB) Is a Thyroid Hormone-regulated Gene in the Developing Central Nervous System" @default.
• W2023999213 cites W1531600133 @default.
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