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Daniel C Factor - One of the best experts on this subject based on the ideXlab platform.
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accumulation of 8 9 unsaturated sterols drives Oligodendrocyte formation and remyelination
Nature, 2018Co-Authors: Zita Hubler, Dharmaraja Allimuthu, Ilya Bederman, Matthew S Elitt, Mayur Madhavan, Kevin C Allan, Elizabeth H Shick, Eric Garrison, Molly Karl, Daniel C FactorAbstract:Regeneration of myelin is mediated by Oligodendrocyte progenitor cells-an abundant stem cell population in the central nervous system (CNS) and the principal source of new myelinating Oligodendrocytes. Loss of myelin-producing Oligodendrocytes in the CNS underlies a number of neurological diseases, including multiple sclerosis and diverse genetic diseases1-3. High-throughput chemical screening approaches have been used to identify small molecules that stimulate the formation of Oligodendrocytes from Oligodendrocyte progenitor cells and functionally enhance remyelination in vivo4-10. Here we show that a wide range of these pro-myelinating small molecules function not through their canonical targets but by directly inhibiting CYP51, TM7SF2, or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes Oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to Oligodendrocyte progenitor cells in purified form whereas analogous sterols that lack this structural feature have no effect. Collectively, our results define a unifying sterol-based mechanism of action for most known small-molecule enhancers of Oligodendrocyte formation and highlight specific targets to propel the development of optimal remyelinating therapeutics.
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accumulation of 8 9 unsaturated sterols drives Oligodendrocyte formation and remyelination
Nature, 2018Co-Authors: Zita Hubler, Dharmaraja Allimuthu, Ilya Bederman, Matthew S Elitt, Mayur Madhavan, Kevin C Allan, Elizabeth H Shick, Eric Garrison, Molly Karl, Daniel C FactorAbstract:Regeneration of myelin is mediated by Oligodendrocyte progenitor cells—an abundant stem cell population in the central nervous system (CNS) and the principal source of new myelinating Oligodendrocytes. Loss of myelin-producing Oligodendrocytes in the CNS underlies a number of neurological diseases, including multiple sclerosis and diverse genetic diseases1–3. High-throughput chemical screening approaches have been used to identify small molecules that stimulate the formation of Oligodendrocytes from Oligodendrocyte progenitor cells and functionally enhance remyelination in vivo4–10. Here we show that a wide range of these pro-myelinating small molecules function not through their canonical targets but by directly inhibiting CYP51, TM7SF2, or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes Oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to Oligodendrocyte progenitor cells in purified form whereas analogous sterols that lack this structural feature have no effect. Collectively, our results define a unifying sterol-based mechanism of action for most known small-molecule enhancers of Oligodendrocyte formation and highlight specific targets to propel the development of optimal remyelinating therapeutics. Many small molecules that stimulate Oligodendrocyte formation act not through their canonical pathways but by inhibiting enzymes within the cholesterol biosynthesis pathway and thereby inducing the accumulation of 8,9-unsaturated sterols.
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transcription factor mediated reprogramming of fibroblasts to expandable myelinogenic Oligodendrocyte progenitor cells
Nature Biotechnology, 2013Co-Authors: Fadi J Najm, Robert H. Miller, Daniel C Factor, Angela M Lager, Anita Zaremba, Krysta Wyatt, Andrew V Caprariello, Robert T Karl, Tadao Maeda, Paul J TesarAbstract:Two studies show direct conversion of mouse embryonic fibroblasts to Oligodendrocyte progenitor cells capable of generating myelinating Oligodendrocytes.
J. Puymirat - One of the best experts on this subject based on the ideXlab platform.
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Posttranscriptional regulation of oligodendroglial thyroid hormone (T3) receptor beta 1 by T3.
International Journal of Developmental Neuroscience, 1998Co-Authors: D. Baas, J. Puymirat, Ll SarlieveAbstract:3,5,3'-triiodo-L-thyronine interacts with the genome by binding and activating nuclear 3,5,3'-triiodo-L-thyronine receptors. To determine how in secondary Oligodendrocyte cultures, exogenous 3,5,3'-triiodo-L-thyronine influences the expression of different 3,5,3'-triiodo-L-thyronine receptor isoforms, we studied the regulation of alpha 1, alpha 2 and beta 1 3,5,3'-triiodo-L-thyronine receptor mRNAs. In culture, we find that beta 1, 3,5,3'-triiodo-L-thyronine receptor mRNA, but not alpha 1 and alpha 2 3,5,3'-triiodo-L-thyronine receptor mRNAs, is up-regulated by 3,5,3'-triiodo-L-thyronine in a time and dose dependent manner. In addition, we present evidence indicating that beta 1 3,5,3'-triiodo-L-thyronine receptor expression is posttranscriptionally regulated by 3,5,3'-triiodo-L-thyronine. Previous studies from our laboratory and others have shown that in the rat Oligodendrocyte lineage, 3,5,3'-triiodo-L-thyronine receptors alpha 1 and alpha 2 were expressed in both early progenitor cells and mature Oligodendrocytes. In contrast, beta 1 3,5,3'-triiodo-L-thyronine receptor was found to be expressed only in mature Oligodendrocytes. This suggests that thyroid hormone may influence Oligodendrocyte differentiation and maturation via 3,5,3'-triiodo-L-thyronine receptor beta 1, which is expressed only in Oligodendrocytes and not in progenitor cells. We therefore show that this effect is indirect and is mediated by 3,5,3'-triiodo-L-thyronine which acts posttranscriptionally on the 3,5,3'-triiodo-L-thyronine receptor beta 1 gene.3,5,3'-triiodo-L-thyronine interacts with the genome by binding and activating nuclear 3,5,3'-triiodo-L-thyronine receptors. To determine how in secondary Oligodendrocyte cultures, exogenous 3,5,3'-triiodo-L-thyronine influences the expression of different 3,5,3'-triiodo-L-thyronine receptor isoforms, we studied the regulation of alpha 1, alpha 2 and beta 1 3,5,3'-triiodo-L-thyronine receptor mRNAs. In culture, we find that beta 1, 3,5,3'-triiodo-L-thyronine receptor mRNA, but not alpha 1 and alpha 2 3,5,3'-triiodo-L-thyronine receptor mRNAs, is up-regulated by 3,5,3'-triiodo-L-thyronine in a time and dose dependent manner. In addition, we present evidence indicating that beta 1 3,5,3'-triiodo-L-thyronine receptor expression is posttranscriptionally regulated by 3,5,3'-triiodo-L-thyronine. Previous studies from our laboratory and others have shown that in the rat Oligodendrocyte lineage, 3,5,3'-triiodo-L-thyronine receptors alpha 1 and alpha 2 were expressed in both early progenitor cells and mature Oligodendrocytes. In contrast, beta 1 3,5,3'-triiodo-L-thyronine receptor was found to be expressed only in mature Oligodendrocytes. This suggests that thyroid hormone may influence Oligodendrocyte differentiation and maturation via 3,5,3'-triiodo-L-thyronine receptor beta 1, which is expressed only in Oligodendrocytes and not in progenitor cells. We therefore show that this effect is indirect and is mediated by 3,5,3'-triiodo-L-thyronine which acts posttranscriptionally on the 3,5,3'-triiodo-L-thyronine receptor beta 1 gene.
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Oligodendrocyte maturation and progenitor cell proliferation are independently regulated by thyroid hormone.
Glia, 1997Co-Authors: D. Baas, D. Bourbeau, Ll Sarlieve, Me Ittel, Jh Dussault, J. PuymiratAbstract:The development of Oligodendrocyte progenitor cells is regulated by epigenetic factors which control their proliferation and differentiation. When Oligodendrocyte progenitor cells, purified on a Percoll centrifugation gradient from neonate rat brain, are cultured in serum-free medium in the presence of platelet-derived-growth factor (PDGF), they divide and their differentiation is delayed. Triiodothyronine (T3) treatment of progenitor cells blocks their proliferation and induces their differentiation into Oligodendrocytes. T3 also induces morphological differentiation of Oligodendrocytes as indicated by the marked increase in the length of Oligodendrocyte processes. To determine whether the effects of T3 on progenitor cell proliferation and Oligodendrocyte maturation are causally related, or instead, are independent, we examined the influence of T3 on secondary cultures of postmitotic Oligodendrocytes. We show that T3 increases morphological and functional maturation of postmitotic Oligodendrocytes as indicated by a well developed network of branched processes and by the expression of myelin/Oligodendrocyte glycoprotein (MOG) and glutamine synthetase (GS). T3 increases glutamine synthetase activity and its message level after a lag period of 24-48 h, and these levels increase through a posttranscriptional event. In contrast, no effect of T3 was observed on myelin basic protein (MBP) gene expression as determined by Northern blot analysis. Our results indicate that thyroid hormones participate in the control of the progenitor cell proliferation and differentiation as well as in Oligodendrocyte maturation and that these two T3-regulated events are independent.The development of Oligodendrocyte progenitor cells is regulated by epigenetic factors which control their proliferation and differentiation. When Oligodendrocyte progenitor cells, purified on a Percoll centrifugation gradient from neonate rat brain, are cultured in serum-free medium in the presence of platelet-derived-growth factor (PDGF), they divide and their differentiation is delayed. Triiodothyronine (T3) treatment of progenitor cells blocks their proliferation and induces their differentiation into Oligodendrocytes. T3 also induces morphological differentiation of Oligodendrocytes as indicated by the marked increase in the length of Oligodendrocyte processes. To determine whether the effects of T3 on progenitor cell proliferation and Oligodendrocyte maturation are causally related, or instead, are independent, we examined the influence of T3 on secondary cultures of postmitotic Oligodendrocytes. We show that T3 increases morphological and functional maturation of postmitotic Oligodendrocytes as indicated by a well developed network of branched processes and by the expression of myelin/Oligodendrocyte glycoprotein (MOG) and glutamine synthetase (GS). T3 increases glutamine synthetase activity and its message level after a lag period of 24-48 h, and these levels increase through a posttranscriptional event. In contrast, no effect of T3 was observed on myelin basic protein (MBP) gene expression as determined by Northern blot analysis. Our results indicate that thyroid hormones participate in the control of the progenitor cell proliferation and differentiation as well as in Oligodendrocyte maturation and that these two T3-regulated events are independent.
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Expression of alpha and beta thyroid receptors during Oligodendrocyte differentiation.
NeuroReport, 1994Co-Authors: D. Baas, D. Bourbeau, Ll Sarlieve, Jh Dussault, Jl Carre, J. PuymiratAbstract:To determine which thyroid receptor (TR) isoforms are expressed during Oligodendrocyte differentiation, we studied the expression of the mRNAs encoding two alpha (alpha 1 and alpha 2) and one beta (beta 1) TR isoforms in a bipotential Oligodendrocyte-type 2-astrocyte (O-2A) progenitor cell line (CG-4) as well as in rat O-2A progenitor cells and Oligodendrocytes. O-2A progenitor cells expressed only TR alpha-mRNAs, whereas Oligodendrocytes and type 2-astrocytes also expressed TR beta 1-mRNAs. The differential expression of alpha 1 and beta 1 TRs suggests specific functions for both types of TRs during Oligodendrocyte differentiation. We present evidence for a possible role of TR alpha 1 in the effect of thyroid hormones on the proliferation of CG-4 cells maintained as progenitor cells.To determine which thyroid receptor (TR) isoforms are expressed during Oligodendrocyte differentiation, we studied the expression of the mRNAs encoding two alpha (alpha 1 and alpha 2) and one beta (beta 1) TR isoforms in a bipotential Oligodendrocyte-type 2-astrocyte (O-2A) progenitor cell line (CG-4) as well as in rat O-2A progenitor cells and Oligodendrocytes. O-2A progenitor cells expressed only TR alpha-mRNAs, whereas Oligodendrocytes and type 2-astrocytes also expressed TR beta 1-mRNAs. The differential expression of alpha 1 and beta 1 TRs suggests specific functions for both types of TRs during Oligodendrocyte differentiation. We present evidence for a possible role of TR alpha 1 in the effect of thyroid hormones on the proliferation of CG-4 cells maintained as progenitor cells.
Samuel F Hunter - One of the best experts on this subject based on the ideXlab platform.
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culture methods for Oligodendrocyte cell lines and Oligodendrocyte type 2 astrocyte lineage cells
Methods in Neurosciences, 1990Co-Authors: Jane E Bottenstein, Samuel F HunterAbstract:Publisher Summary This chapter gives detailed methods for culturing Oligodendrocyte cell lines and dissociated rat brain cells of the Oligodendrocyte-type 2 astrocyte (O-2A) lineage. Cultured cells expressing an Oligodendrocyte phenotype are useful models for understanding many aspects of normal central nervous system (CNS) development and myelination. Neonatal and older brain tissue sources result in neuron-free cultures after a few days. The use of serum-free chemically defined medium significantly depletes the cultures of contaminating fibroblast and meningeal cells, and it favors the development of Oligodendrocytes. To increase yields of O-2A lineage cells, neonatal O-2A progenitor cells can be initially expanded with neuronal cell line-derived growth factors. Removal of the growth factors results in enhanced differentiation into Oligodendrocytes in serum-free conditions or, alternatively, induces differentiation into type 2 astrocytes in serum-containing conditions. The type 2 astrocyte-inducing factor present in serum has not yet been isolated and characterized, although, ciliary neuronotropic factor has been shown to act similarly. The chapter also discusses methods for preparing enriched cultures of O-2A lineage cells or mature Oligodendrocytes.
D. Baas - One of the best experts on this subject based on the ideXlab platform.
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Posttranscriptional regulation of oligodendroglial thyroid hormone (T3) receptor beta 1 by T3.
International Journal of Developmental Neuroscience, 1998Co-Authors: D. Baas, J. Puymirat, Ll SarlieveAbstract:3,5,3'-triiodo-L-thyronine interacts with the genome by binding and activating nuclear 3,5,3'-triiodo-L-thyronine receptors. To determine how in secondary Oligodendrocyte cultures, exogenous 3,5,3'-triiodo-L-thyronine influences the expression of different 3,5,3'-triiodo-L-thyronine receptor isoforms, we studied the regulation of alpha 1, alpha 2 and beta 1 3,5,3'-triiodo-L-thyronine receptor mRNAs. In culture, we find that beta 1, 3,5,3'-triiodo-L-thyronine receptor mRNA, but not alpha 1 and alpha 2 3,5,3'-triiodo-L-thyronine receptor mRNAs, is up-regulated by 3,5,3'-triiodo-L-thyronine in a time and dose dependent manner. In addition, we present evidence indicating that beta 1 3,5,3'-triiodo-L-thyronine receptor expression is posttranscriptionally regulated by 3,5,3'-triiodo-L-thyronine. Previous studies from our laboratory and others have shown that in the rat Oligodendrocyte lineage, 3,5,3'-triiodo-L-thyronine receptors alpha 1 and alpha 2 were expressed in both early progenitor cells and mature Oligodendrocytes. In contrast, beta 1 3,5,3'-triiodo-L-thyronine receptor was found to be expressed only in mature Oligodendrocytes. This suggests that thyroid hormone may influence Oligodendrocyte differentiation and maturation via 3,5,3'-triiodo-L-thyronine receptor beta 1, which is expressed only in Oligodendrocytes and not in progenitor cells. We therefore show that this effect is indirect and is mediated by 3,5,3'-triiodo-L-thyronine which acts posttranscriptionally on the 3,5,3'-triiodo-L-thyronine receptor beta 1 gene.3,5,3'-triiodo-L-thyronine interacts with the genome by binding and activating nuclear 3,5,3'-triiodo-L-thyronine receptors. To determine how in secondary Oligodendrocyte cultures, exogenous 3,5,3'-triiodo-L-thyronine influences the expression of different 3,5,3'-triiodo-L-thyronine receptor isoforms, we studied the regulation of alpha 1, alpha 2 and beta 1 3,5,3'-triiodo-L-thyronine receptor mRNAs. In culture, we find that beta 1, 3,5,3'-triiodo-L-thyronine receptor mRNA, but not alpha 1 and alpha 2 3,5,3'-triiodo-L-thyronine receptor mRNAs, is up-regulated by 3,5,3'-triiodo-L-thyronine in a time and dose dependent manner. In addition, we present evidence indicating that beta 1 3,5,3'-triiodo-L-thyronine receptor expression is posttranscriptionally regulated by 3,5,3'-triiodo-L-thyronine. Previous studies from our laboratory and others have shown that in the rat Oligodendrocyte lineage, 3,5,3'-triiodo-L-thyronine receptors alpha 1 and alpha 2 were expressed in both early progenitor cells and mature Oligodendrocytes. In contrast, beta 1 3,5,3'-triiodo-L-thyronine receptor was found to be expressed only in mature Oligodendrocytes. This suggests that thyroid hormone may influence Oligodendrocyte differentiation and maturation via 3,5,3'-triiodo-L-thyronine receptor beta 1, which is expressed only in Oligodendrocytes and not in progenitor cells. We therefore show that this effect is indirect and is mediated by 3,5,3'-triiodo-L-thyronine which acts posttranscriptionally on the 3,5,3'-triiodo-L-thyronine receptor beta 1 gene.
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Oligodendrocyte maturation and progenitor cell proliferation are independently regulated by thyroid hormone.
Glia, 1997Co-Authors: D. Baas, D. Bourbeau, Ll Sarlieve, Me Ittel, Jh Dussault, J. PuymiratAbstract:The development of Oligodendrocyte progenitor cells is regulated by epigenetic factors which control their proliferation and differentiation. When Oligodendrocyte progenitor cells, purified on a Percoll centrifugation gradient from neonate rat brain, are cultured in serum-free medium in the presence of platelet-derived-growth factor (PDGF), they divide and their differentiation is delayed. Triiodothyronine (T3) treatment of progenitor cells blocks their proliferation and induces their differentiation into Oligodendrocytes. T3 also induces morphological differentiation of Oligodendrocytes as indicated by the marked increase in the length of Oligodendrocyte processes. To determine whether the effects of T3 on progenitor cell proliferation and Oligodendrocyte maturation are causally related, or instead, are independent, we examined the influence of T3 on secondary cultures of postmitotic Oligodendrocytes. We show that T3 increases morphological and functional maturation of postmitotic Oligodendrocytes as indicated by a well developed network of branched processes and by the expression of myelin/Oligodendrocyte glycoprotein (MOG) and glutamine synthetase (GS). T3 increases glutamine synthetase activity and its message level after a lag period of 24-48 h, and these levels increase through a posttranscriptional event. In contrast, no effect of T3 was observed on myelin basic protein (MBP) gene expression as determined by Northern blot analysis. Our results indicate that thyroid hormones participate in the control of the progenitor cell proliferation and differentiation as well as in Oligodendrocyte maturation and that these two T3-regulated events are independent.The development of Oligodendrocyte progenitor cells is regulated by epigenetic factors which control their proliferation and differentiation. When Oligodendrocyte progenitor cells, purified on a Percoll centrifugation gradient from neonate rat brain, are cultured in serum-free medium in the presence of platelet-derived-growth factor (PDGF), they divide and their differentiation is delayed. Triiodothyronine (T3) treatment of progenitor cells blocks their proliferation and induces their differentiation into Oligodendrocytes. T3 also induces morphological differentiation of Oligodendrocytes as indicated by the marked increase in the length of Oligodendrocyte processes. To determine whether the effects of T3 on progenitor cell proliferation and Oligodendrocyte maturation are causally related, or instead, are independent, we examined the influence of T3 on secondary cultures of postmitotic Oligodendrocytes. We show that T3 increases morphological and functional maturation of postmitotic Oligodendrocytes as indicated by a well developed network of branched processes and by the expression of myelin/Oligodendrocyte glycoprotein (MOG) and glutamine synthetase (GS). T3 increases glutamine synthetase activity and its message level after a lag period of 24-48 h, and these levels increase through a posttranscriptional event. In contrast, no effect of T3 was observed on myelin basic protein (MBP) gene expression as determined by Northern blot analysis. Our results indicate that thyroid hormones participate in the control of the progenitor cell proliferation and differentiation as well as in Oligodendrocyte maturation and that these two T3-regulated events are independent.
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Expression of alpha and beta thyroid receptors during Oligodendrocyte differentiation.
NeuroReport, 1994Co-Authors: D. Baas, D. Bourbeau, Ll Sarlieve, Jh Dussault, Jl Carre, J. PuymiratAbstract:To determine which thyroid receptor (TR) isoforms are expressed during Oligodendrocyte differentiation, we studied the expression of the mRNAs encoding two alpha (alpha 1 and alpha 2) and one beta (beta 1) TR isoforms in a bipotential Oligodendrocyte-type 2-astrocyte (O-2A) progenitor cell line (CG-4) as well as in rat O-2A progenitor cells and Oligodendrocytes. O-2A progenitor cells expressed only TR alpha-mRNAs, whereas Oligodendrocytes and type 2-astrocytes also expressed TR beta 1-mRNAs. The differential expression of alpha 1 and beta 1 TRs suggests specific functions for both types of TRs during Oligodendrocyte differentiation. We present evidence for a possible role of TR alpha 1 in the effect of thyroid hormones on the proliferation of CG-4 cells maintained as progenitor cells.To determine which thyroid receptor (TR) isoforms are expressed during Oligodendrocyte differentiation, we studied the expression of the mRNAs encoding two alpha (alpha 1 and alpha 2) and one beta (beta 1) TR isoforms in a bipotential Oligodendrocyte-type 2-astrocyte (O-2A) progenitor cell line (CG-4) as well as in rat O-2A progenitor cells and Oligodendrocytes. O-2A progenitor cells expressed only TR alpha-mRNAs, whereas Oligodendrocytes and type 2-astrocytes also expressed TR beta 1-mRNAs. The differential expression of alpha 1 and beta 1 TRs suggests specific functions for both types of TRs during Oligodendrocyte differentiation. We present evidence for a possible role of TR alpha 1 in the effect of thyroid hormones on the proliferation of CG-4 cells maintained as progenitor cells.
Ll Sarlieve - One of the best experts on this subject based on the ideXlab platform.
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Posttranscriptional regulation of oligodendroglial thyroid hormone (T3) receptor beta 1 by T3.
International Journal of Developmental Neuroscience, 1998Co-Authors: D. Baas, J. Puymirat, Ll SarlieveAbstract:3,5,3'-triiodo-L-thyronine interacts with the genome by binding and activating nuclear 3,5,3'-triiodo-L-thyronine receptors. To determine how in secondary Oligodendrocyte cultures, exogenous 3,5,3'-triiodo-L-thyronine influences the expression of different 3,5,3'-triiodo-L-thyronine receptor isoforms, we studied the regulation of alpha 1, alpha 2 and beta 1 3,5,3'-triiodo-L-thyronine receptor mRNAs. In culture, we find that beta 1, 3,5,3'-triiodo-L-thyronine receptor mRNA, but not alpha 1 and alpha 2 3,5,3'-triiodo-L-thyronine receptor mRNAs, is up-regulated by 3,5,3'-triiodo-L-thyronine in a time and dose dependent manner. In addition, we present evidence indicating that beta 1 3,5,3'-triiodo-L-thyronine receptor expression is posttranscriptionally regulated by 3,5,3'-triiodo-L-thyronine. Previous studies from our laboratory and others have shown that in the rat Oligodendrocyte lineage, 3,5,3'-triiodo-L-thyronine receptors alpha 1 and alpha 2 were expressed in both early progenitor cells and mature Oligodendrocytes. In contrast, beta 1 3,5,3'-triiodo-L-thyronine receptor was found to be expressed only in mature Oligodendrocytes. This suggests that thyroid hormone may influence Oligodendrocyte differentiation and maturation via 3,5,3'-triiodo-L-thyronine receptor beta 1, which is expressed only in Oligodendrocytes and not in progenitor cells. We therefore show that this effect is indirect and is mediated by 3,5,3'-triiodo-L-thyronine which acts posttranscriptionally on the 3,5,3'-triiodo-L-thyronine receptor beta 1 gene.3,5,3'-triiodo-L-thyronine interacts with the genome by binding and activating nuclear 3,5,3'-triiodo-L-thyronine receptors. To determine how in secondary Oligodendrocyte cultures, exogenous 3,5,3'-triiodo-L-thyronine influences the expression of different 3,5,3'-triiodo-L-thyronine receptor isoforms, we studied the regulation of alpha 1, alpha 2 and beta 1 3,5,3'-triiodo-L-thyronine receptor mRNAs. In culture, we find that beta 1, 3,5,3'-triiodo-L-thyronine receptor mRNA, but not alpha 1 and alpha 2 3,5,3'-triiodo-L-thyronine receptor mRNAs, is up-regulated by 3,5,3'-triiodo-L-thyronine in a time and dose dependent manner. In addition, we present evidence indicating that beta 1 3,5,3'-triiodo-L-thyronine receptor expression is posttranscriptionally regulated by 3,5,3'-triiodo-L-thyronine. Previous studies from our laboratory and others have shown that in the rat Oligodendrocyte lineage, 3,5,3'-triiodo-L-thyronine receptors alpha 1 and alpha 2 were expressed in both early progenitor cells and mature Oligodendrocytes. In contrast, beta 1 3,5,3'-triiodo-L-thyronine receptor was found to be expressed only in mature Oligodendrocytes. This suggests that thyroid hormone may influence Oligodendrocyte differentiation and maturation via 3,5,3'-triiodo-L-thyronine receptor beta 1, which is expressed only in Oligodendrocytes and not in progenitor cells. We therefore show that this effect is indirect and is mediated by 3,5,3'-triiodo-L-thyronine which acts posttranscriptionally on the 3,5,3'-triiodo-L-thyronine receptor beta 1 gene.
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Oligodendrocyte maturation and progenitor cell proliferation are independently regulated by thyroid hormone.
Glia, 1997Co-Authors: D. Baas, D. Bourbeau, Ll Sarlieve, Me Ittel, Jh Dussault, J. PuymiratAbstract:The development of Oligodendrocyte progenitor cells is regulated by epigenetic factors which control their proliferation and differentiation. When Oligodendrocyte progenitor cells, purified on a Percoll centrifugation gradient from neonate rat brain, are cultured in serum-free medium in the presence of platelet-derived-growth factor (PDGF), they divide and their differentiation is delayed. Triiodothyronine (T3) treatment of progenitor cells blocks their proliferation and induces their differentiation into Oligodendrocytes. T3 also induces morphological differentiation of Oligodendrocytes as indicated by the marked increase in the length of Oligodendrocyte processes. To determine whether the effects of T3 on progenitor cell proliferation and Oligodendrocyte maturation are causally related, or instead, are independent, we examined the influence of T3 on secondary cultures of postmitotic Oligodendrocytes. We show that T3 increases morphological and functional maturation of postmitotic Oligodendrocytes as indicated by a well developed network of branched processes and by the expression of myelin/Oligodendrocyte glycoprotein (MOG) and glutamine synthetase (GS). T3 increases glutamine synthetase activity and its message level after a lag period of 24-48 h, and these levels increase through a posttranscriptional event. In contrast, no effect of T3 was observed on myelin basic protein (MBP) gene expression as determined by Northern blot analysis. Our results indicate that thyroid hormones participate in the control of the progenitor cell proliferation and differentiation as well as in Oligodendrocyte maturation and that these two T3-regulated events are independent.The development of Oligodendrocyte progenitor cells is regulated by epigenetic factors which control their proliferation and differentiation. When Oligodendrocyte progenitor cells, purified on a Percoll centrifugation gradient from neonate rat brain, are cultured in serum-free medium in the presence of platelet-derived-growth factor (PDGF), they divide and their differentiation is delayed. Triiodothyronine (T3) treatment of progenitor cells blocks their proliferation and induces their differentiation into Oligodendrocytes. T3 also induces morphological differentiation of Oligodendrocytes as indicated by the marked increase in the length of Oligodendrocyte processes. To determine whether the effects of T3 on progenitor cell proliferation and Oligodendrocyte maturation are causally related, or instead, are independent, we examined the influence of T3 on secondary cultures of postmitotic Oligodendrocytes. We show that T3 increases morphological and functional maturation of postmitotic Oligodendrocytes as indicated by a well developed network of branched processes and by the expression of myelin/Oligodendrocyte glycoprotein (MOG) and glutamine synthetase (GS). T3 increases glutamine synthetase activity and its message level after a lag period of 24-48 h, and these levels increase through a posttranscriptional event. In contrast, no effect of T3 was observed on myelin basic protein (MBP) gene expression as determined by Northern blot analysis. Our results indicate that thyroid hormones participate in the control of the progenitor cell proliferation and differentiation as well as in Oligodendrocyte maturation and that these two T3-regulated events are independent.
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Expression of alpha and beta thyroid receptors during Oligodendrocyte differentiation.
NeuroReport, 1994Co-Authors: D. Baas, D. Bourbeau, Ll Sarlieve, Jh Dussault, Jl Carre, J. PuymiratAbstract:To determine which thyroid receptor (TR) isoforms are expressed during Oligodendrocyte differentiation, we studied the expression of the mRNAs encoding two alpha (alpha 1 and alpha 2) and one beta (beta 1) TR isoforms in a bipotential Oligodendrocyte-type 2-astrocyte (O-2A) progenitor cell line (CG-4) as well as in rat O-2A progenitor cells and Oligodendrocytes. O-2A progenitor cells expressed only TR alpha-mRNAs, whereas Oligodendrocytes and type 2-astrocytes also expressed TR beta 1-mRNAs. The differential expression of alpha 1 and beta 1 TRs suggests specific functions for both types of TRs during Oligodendrocyte differentiation. We present evidence for a possible role of TR alpha 1 in the effect of thyroid hormones on the proliferation of CG-4 cells maintained as progenitor cells.To determine which thyroid receptor (TR) isoforms are expressed during Oligodendrocyte differentiation, we studied the expression of the mRNAs encoding two alpha (alpha 1 and alpha 2) and one beta (beta 1) TR isoforms in a bipotential Oligodendrocyte-type 2-astrocyte (O-2A) progenitor cell line (CG-4) as well as in rat O-2A progenitor cells and Oligodendrocytes. O-2A progenitor cells expressed only TR alpha-mRNAs, whereas Oligodendrocytes and type 2-astrocytes also expressed TR beta 1-mRNAs. The differential expression of alpha 1 and beta 1 TRs suggests specific functions for both types of TRs during Oligodendrocyte differentiation. We present evidence for a possible role of TR alpha 1 in the effect of thyroid hormones on the proliferation of CG-4 cells maintained as progenitor cells.
