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Michael Wegner - One of the best experts on this subject based on the ideXlab platform.
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formation of the node of ranvier by schwann cells is under control of Transcription Factor Sox10
Glia, 2021Co-Authors: Annalena Saur, Matthias Weider, Franziska Frob, Michael WegnerAbstract:The Transcription Factor Sox10 is an essential regulator of genes that code for structural components of the myelin sheath and for lipid metabolic enzymes in both types of myelinating glia in the central and peripheral nervous systems. In an attempt to characterize additional Sox10 target genes in Schwann cells, we identified in this study a strong influence of Sox10 on the expression of genes associated with adhesion in the MSC80 Schwann cell line. These included the genes for Gliomedin, Neuronal cell adhesion molecule and Neurofascin that together constitute essential Schwann cell contributions to paranode and node of Ranvier. Using bioinformatics and molecular biology techniques we provide evidence that Sox10 directly activates these genes by binding to conserved regulatory regions. For activation, Sox10 cooperates with Krox20, a Transcription Factor previously identified as the central regulator of Schwann cell myelination. Both the activating function of Sox10 as well as its cooperation with Krox20 were confirmed in vivo. We conclude that the employment of Sox10 and Krox20 as regulators of structural myelin sheath components and genes associated with the node of Ranvier is one way of ensuring a biologically meaningful coordinated formation of both structures during peripheral myelination.
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the Transcription Factor Sox10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland
Scientific Reports, 2020Co-Authors: Svenja Mertelmeyer, Matthias Weider, Claus C Stolt, Franziska Frob, Tina Baroti, Simone Reiprich, Kay Uwe Wagner, Michael WegnerAbstract:The high mobility group-domain containing Transcription Factor Sox10 is an essential regulator of developmental processes and homeostasis in the neural crest, several neural crest-derived lineages and myelinating glia. Recent studies have also implicated Sox10 as an important Factor in mammary stem and precursor cells. Here we employ a series of mouse mutants with constitutive and conditional Sox10 deficiencies to show that Sox10 has multiple functions in the developing mammary gland. While there is no indication for a requirement of Sox10 in the specification of the mammary placode or descending mammary bud, it is essential for both the prenatal hormone-independent as well as the pubertal hormone-dependent branching of the mammary epithelium and for proper alveologenesis during pregnancy. It furthermore acts in a dosage-dependent manner. Sox10 also plays a role during the involution process at the end of the lactation period. Whereas its effect on epithelial branching and alveologenesis are likely causally related to its function in mammary stem and precursor cells, this is not the case for its function during involution where Sox10 seems to work at least in part through regulation of the miR-424(322)/503 cluster.
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Transcription Factor Sox10 regulates oligodendroglial sox9 levels via micrornas
Glia, 2017Co-Authors: Simone Reiprich, Matthias Weider, Christian Schmitt, Melanie Küspert, Tina Baroti, Martina Cantone, Jan Wittstatt, Julio Vera, Michael WegnerAbstract:During development of myelin-forming oligodendrocytes in the central nervous system the two closely related Transcription Factors Sox9 and Sox10 play essential roles that are partly shared and partly unique. Whereas Sox9 primarily functions during oligodendroglial specification, Sox10 is uniquely required to induce terminal differentiation and myelination. During this process, Sox10 protein levels rise substantially. As this coincides with a reciprocal decrease in Sox9, we postulated that Sox10 influences Sox9 amounts in differentiating oligodendrocytes. Here we show that Sox9 levels are indeed inversely coupled to Sox10 levels such that Sox10 deletion in oligodendroglial cells evokes a reciprocal increase in Sox9. We furthermore provide evidence that this coupling involves upregulation of microRNAs miR335 and miR338 as direct Transcriptional targets of Sox10. The two microRNAs in turn recognize the 3′-UTR of Sox9 mRNA and may thereby reduce Sox9 protein levels postTranscriptionally in oligodendroglial cells. Such a mechanism may enable oligodendroglial cells to adapt the ratio of both related Sox proteins in a manner required for successful lineage progression and differentiation. Mathematical modeling furthermore shows that the identified regulatory circuit has the potential to convert a transient stimulus into an irreversible switch of cellular properties and may thus contribute to terminal differentiation of oligodendrocytes.
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Elevated In Vivo Levels of a Single Transcription Factor Directly Convert Satellite Glia into Oligodendrocyte-like Cells
PLoS Genetics, 2015Co-Authors: Matthias Weider, Amélie Wegener, Christian Schmitt, Melanie Küspert, Simone Hillgärtner, Michael R Bösl, Irm Hermans-borgmeyer, Brahim Nait-oumesmar, Michael WegnerAbstract:Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the Transcription Factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, Olig1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dor-sal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.
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targeted deletion of Sox10 by wnt1 cre defects neuronal migration and projection in the mouse inner ear
PLOS ONE, 2014Co-Authors: Yanyan Mao, Michael Wegner, Simone Reiprich, Bernd FritzschAbstract:Sensory nerves of the brainstem are mostly composed of placode-derived neurons, neural crest-derived neurons and neural crest-derived Schwann cells. This mixed origin of cells has made it difficult to dissect interdependence for fiber guidance. Inner ear-derived neurons are known to connect to the brain after delayed loss of Schwann cells in ErbB2 mutants. However, the ErbB2 mutant related alterations in the ear and the brain compound interpretation of the data. We present here a new model to evaluate exclusively the effect of Schwann cell loss on inner ear innervation. Conditional deletion of the neural crest specific Transcription Factor, Sox10, using the rhombic lip/neural crest specific Wnt1-cre driver spares Sox10 expression in the ear. We confirm that neural crest-derived cells provide a stop signal for migrating spiral ganglion neurons. In the absence of Schwann cells, spiral ganglion neurons migrate into the center of the cochlea and even out of the ear toward the brain. Spiral ganglion neuron afferent processes reach the organ of Corti, but many afferent fibers bypass the organ of Corti to enter the lateral wall of the cochlea. In contrast to this peripheral disorganization, the central projection to cochlear nuclei is normal. Compared to ErbB2 mutants, conditional Sox10 mutants have limited cell death in spiral ganglion neurons, indicating that the absence of Schwann cells alone contributes little to the embryonic survival of neurons. These data suggest that neural crest-derived cells are dispensable for all central and some peripheral targeting of inner ear neurons. However, Schwann cells provide a stop signal for migratory spiral ganglion neurons and facilitate proper targeting of the organ of Corti by spiral ganglion afferents.
Matthias Weider - One of the best experts on this subject based on the ideXlab platform.
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formation of the node of ranvier by schwann cells is under control of Transcription Factor Sox10
Glia, 2021Co-Authors: Annalena Saur, Matthias Weider, Franziska Frob, Michael WegnerAbstract:The Transcription Factor Sox10 is an essential regulator of genes that code for structural components of the myelin sheath and for lipid metabolic enzymes in both types of myelinating glia in the central and peripheral nervous systems. In an attempt to characterize additional Sox10 target genes in Schwann cells, we identified in this study a strong influence of Sox10 on the expression of genes associated with adhesion in the MSC80 Schwann cell line. These included the genes for Gliomedin, Neuronal cell adhesion molecule and Neurofascin that together constitute essential Schwann cell contributions to paranode and node of Ranvier. Using bioinformatics and molecular biology techniques we provide evidence that Sox10 directly activates these genes by binding to conserved regulatory regions. For activation, Sox10 cooperates with Krox20, a Transcription Factor previously identified as the central regulator of Schwann cell myelination. Both the activating function of Sox10 as well as its cooperation with Krox20 were confirmed in vivo. We conclude that the employment of Sox10 and Krox20 as regulators of structural myelin sheath components and genes associated with the node of Ranvier is one way of ensuring a biologically meaningful coordinated formation of both structures during peripheral myelination.
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the Transcription Factor Sox10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland
Scientific Reports, 2020Co-Authors: Svenja Mertelmeyer, Matthias Weider, Claus C Stolt, Franziska Frob, Tina Baroti, Simone Reiprich, Kay Uwe Wagner, Michael WegnerAbstract:The high mobility group-domain containing Transcription Factor Sox10 is an essential regulator of developmental processes and homeostasis in the neural crest, several neural crest-derived lineages and myelinating glia. Recent studies have also implicated Sox10 as an important Factor in mammary stem and precursor cells. Here we employ a series of mouse mutants with constitutive and conditional Sox10 deficiencies to show that Sox10 has multiple functions in the developing mammary gland. While there is no indication for a requirement of Sox10 in the specification of the mammary placode or descending mammary bud, it is essential for both the prenatal hormone-independent as well as the pubertal hormone-dependent branching of the mammary epithelium and for proper alveologenesis during pregnancy. It furthermore acts in a dosage-dependent manner. Sox10 also plays a role during the involution process at the end of the lactation period. Whereas its effect on epithelial branching and alveologenesis are likely causally related to its function in mammary stem and precursor cells, this is not the case for its function during involution where Sox10 seems to work at least in part through regulation of the miR-424(322)/503 cluster.
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Transcription Factor Sox10 regulates oligodendroglial sox9 levels via micrornas
Glia, 2017Co-Authors: Simone Reiprich, Matthias Weider, Christian Schmitt, Melanie Küspert, Tina Baroti, Martina Cantone, Jan Wittstatt, Julio Vera, Michael WegnerAbstract:During development of myelin-forming oligodendrocytes in the central nervous system the two closely related Transcription Factors Sox9 and Sox10 play essential roles that are partly shared and partly unique. Whereas Sox9 primarily functions during oligodendroglial specification, Sox10 is uniquely required to induce terminal differentiation and myelination. During this process, Sox10 protein levels rise substantially. As this coincides with a reciprocal decrease in Sox9, we postulated that Sox10 influences Sox9 amounts in differentiating oligodendrocytes. Here we show that Sox9 levels are indeed inversely coupled to Sox10 levels such that Sox10 deletion in oligodendroglial cells evokes a reciprocal increase in Sox9. We furthermore provide evidence that this coupling involves upregulation of microRNAs miR335 and miR338 as direct Transcriptional targets of Sox10. The two microRNAs in turn recognize the 3′-UTR of Sox9 mRNA and may thereby reduce Sox9 protein levels postTranscriptionally in oligodendroglial cells. Such a mechanism may enable oligodendroglial cells to adapt the ratio of both related Sox proteins in a manner required for successful lineage progression and differentiation. Mathematical modeling furthermore shows that the identified regulatory circuit has the potential to convert a transient stimulus into an irreversible switch of cellular properties and may thus contribute to terminal differentiation of oligodendrocytes.
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Elevated In Vivo Levels of a Single Transcription Factor Directly Convert Satellite Glia into Oligodendrocyte-like Cells
PLoS Genetics, 2015Co-Authors: Matthias Weider, Amélie Wegener, Christian Schmitt, Melanie Küspert, Simone Hillgärtner, Michael R Bösl, Irm Hermans-borgmeyer, Brahim Nait-oumesmar, Michael WegnerAbstract:Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the Transcription Factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, Olig1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dor-sal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.
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chromatin remodeling Factor brg1 is required for schwann cell differentiation and myelination
Developmental Cell, 2012Co-Authors: Matthias Weider, Melanie Küspert, Simone Hillgärtner, Thomas Kosian, Jana Muller, Michael R Vogl, Melanie Bischof, Julia Hornig, Kristina Loy, Ernst R TammAbstract:Schwann cells produce myelin sheaths and thereby permit rapid saltatory conductance in the vertebrate peripheral nervous system. Their stepwise differentiation from neural crest cells is driven by a defined set of Transcription Factors. How this is linked to chromatin changes is not well understood. Here we show that the glial Transcription Factor Sox10 functions in Schwann cells by recruiting Brg1-containing chromatin-remodeling complexes via Baf60a to regulatory regions of Oct6 and Krox20 genes. It thereby stimulates expression of these Transcriptional regulators that then cooperate with Sox10 to convert immature into myelinating Schwann cells. The functional interaction between Sox10 and Brg1 is evident from gain- and loss-of-function studies, similar neuropathies in the corresponding mouse mutants, and an aggravated neuropathy in compound mutants. Our results demonstrate that the Transcription Factor-mediated recruitment of the chromatin-remodeling machinery to specific genomic loci is an essential driving force for Schwann cell differentiation and myelination.
Melanie Küspert - One of the best experts on this subject based on the ideXlab platform.
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Transcription Factor Sox10 regulates oligodendroglial sox9 levels via micrornas
Glia, 2017Co-Authors: Simone Reiprich, Matthias Weider, Christian Schmitt, Melanie Küspert, Tina Baroti, Martina Cantone, Jan Wittstatt, Julio Vera, Michael WegnerAbstract:During development of myelin-forming oligodendrocytes in the central nervous system the two closely related Transcription Factors Sox9 and Sox10 play essential roles that are partly shared and partly unique. Whereas Sox9 primarily functions during oligodendroglial specification, Sox10 is uniquely required to induce terminal differentiation and myelination. During this process, Sox10 protein levels rise substantially. As this coincides with a reciprocal decrease in Sox9, we postulated that Sox10 influences Sox9 amounts in differentiating oligodendrocytes. Here we show that Sox9 levels are indeed inversely coupled to Sox10 levels such that Sox10 deletion in oligodendroglial cells evokes a reciprocal increase in Sox9. We furthermore provide evidence that this coupling involves upregulation of microRNAs miR335 and miR338 as direct Transcriptional targets of Sox10. The two microRNAs in turn recognize the 3′-UTR of Sox9 mRNA and may thereby reduce Sox9 protein levels postTranscriptionally in oligodendroglial cells. Such a mechanism may enable oligodendroglial cells to adapt the ratio of both related Sox proteins in a manner required for successful lineage progression and differentiation. Mathematical modeling furthermore shows that the identified regulatory circuit has the potential to convert a transient stimulus into an irreversible switch of cellular properties and may thus contribute to terminal differentiation of oligodendrocytes.
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Elevated In Vivo Levels of a Single Transcription Factor Directly Convert Satellite Glia into Oligodendrocyte-like Cells
PLoS Genetics, 2015Co-Authors: Matthias Weider, Amélie Wegener, Christian Schmitt, Melanie Küspert, Simone Hillgärtner, Michael R Bösl, Irm Hermans-borgmeyer, Brahim Nait-oumesmar, Michael WegnerAbstract:Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the Transcription Factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, Olig1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dor-sal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.
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chromatin remodeling Factor brg1 is required for schwann cell differentiation and myelination
Developmental Cell, 2012Co-Authors: Matthias Weider, Melanie Küspert, Simone Hillgärtner, Thomas Kosian, Jana Muller, Michael R Vogl, Melanie Bischof, Julia Hornig, Kristina Loy, Ernst R TammAbstract:Schwann cells produce myelin sheaths and thereby permit rapid saltatory conductance in the vertebrate peripheral nervous system. Their stepwise differentiation from neural crest cells is driven by a defined set of Transcription Factors. How this is linked to chromatin changes is not well understood. Here we show that the glial Transcription Factor Sox10 functions in Schwann cells by recruiting Brg1-containing chromatin-remodeling complexes via Baf60a to regulatory regions of Oct6 and Krox20 genes. It thereby stimulates expression of these Transcriptional regulators that then cooperate with Sox10 to convert immature into myelinating Schwann cells. The functional interaction between Sox10 and Brg1 is evident from gain- and loss-of-function studies, similar neuropathies in the corresponding mouse mutants, and an aggravated neuropathy in compound mutants. Our results demonstrate that the Transcription Factor-mediated recruitment of the chromatin-remodeling machinery to specific genomic loci is an essential driving force for Schwann cell differentiation and myelination.
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desert hedgehog links Transcription Factor Sox10 to perineurial development
The Journal of Neuroscience, 2012Co-Authors: Melanie Küspert, Matthias Weider, Irm Hermansborgmeyer, Jana Muller, Dies Meijer, Michael WegnerAbstract:Schwann cells are the main glial cell type in the PNS. They develop along nerves during embryogenesis and rely on the HMG domain containing Sox10 Transcription Factor for specification, lineage progression, and terminal differentiation. Sox10 deletion in immature Schwann cells caused peripheral nerve defects in mice that were not restricted to this glial cell type, although expression in the nerve and gene loss were. Formation of the perineurium as the protecting sheath was, for instance, heavily compromised. This resembled the defect observed after loss of Desert hedgehog (Dhh) in mice. Here we show that Sox10 activates Dhh expression in Schwann cells via an enhancer that is located in intron 1 of the Dhh gene. Sox10 binds this enhancer in monomeric form via several sites. Mutation of these sites abolishes both Schwann-cell-specific activity and Sox10 responsiveness in vitro and in transgenic mouse embryos. This argues that Sox10 activates Dhh expression by direct binding to the enhancer and by increasing Dhh levels promotes formation of the perineurial sheath. This represents the first mechanism for a non-cell-autonomous function of Sox10 during peripheral nerve development.
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olig2 regulates Sox10 expression in oligodendrocyte precursors through an evolutionary conserved distal enhancer
Nucleic Acids Research, 2011Co-Authors: Melanie Küspert, Michael R Bösl, Alexander Hammer, Michael WegnerAbstract:The HMG-domain Transcription Factor Sox10 is expressed throughout oligodendrocyte development and is an important component of the Transcriptional regulatory network in these myelin-forming CNS glia. Of the known Sox10 regulatory regions, only the evolutionary conserved U2 enhancer in the distal 5′-flank of the Sox10 gene exhibits oligodendroglial activity. We found that U2 was active in oligodendrocyte precursors, but not in mature oligodendrocytes. U2 activity also did not mediate the initial Sox10 induction after specification arguing that Sox10 expression during oligodendroglial development depends on the activity of multiple regulatory regions. The oligodendroglial bHLH Transcription Factor Olig2, but not the closely related Olig1 efficiently activated the U2 enhancer. Olig2 bound U2 directly at several sites including a highly conserved one in the U2 core. Inactivation of this site abolished the oligodendroglial activity of U2 in vivo. In contrast to Olig2, the homeodomain Transcription Factor Nkx6.2 repressed U2 activity. Repression may involve recruitment of Nkx6.2 to U2 and inactivation of Olig2 and other activators by protein–protein interactions. Considering the selective expression of Nkx6.2 at the time of specification and in differentiated oligodendrocytes, Nkx6.2 may be involved in limiting U2 activity to the precursor stage during oligodendrocyte development.
Michael R Bösl - One of the best experts on this subject based on the ideXlab platform.
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Elevated In Vivo Levels of a Single Transcription Factor Directly Convert Satellite Glia into Oligodendrocyte-like Cells
PLoS Genetics, 2015Co-Authors: Matthias Weider, Amélie Wegener, Christian Schmitt, Melanie Küspert, Simone Hillgärtner, Michael R Bösl, Irm Hermans-borgmeyer, Brahim Nait-oumesmar, Michael WegnerAbstract:Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the Transcription Factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, Olig1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dor-sal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.
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Transcription Factor Sox10 orchestrates activity of a neural crest specific enhancer in the vicinity of its gene
Nucleic Acids Research, 2012Co-Authors: Mandy Wahlbuhl, Simone Reiprich, Michael R Bösl, Michael R Vogl, Michael WegnerAbstract:The Sox10 Transcription Factor is a central regulator of vertebrate neural crest and nervous system development. Its expression is likely controlled by multiple enhancer elements, among them U3 (alternatively known as MCS4). Here we analyze U3 activity to obtain deeper insights into Sox10 function and expression in the neural crest and its derivatives. U3 activity strongly depends on the presence of Sox10 that regulates its own expression as commonly observed for important developmental regulators. Sox10 bound directly as monomer to at least three sites in U3, whereas a fourth site preferred dimers. Deletion of these sites efficiently reduced U3 activity in transfected cells and transgenic mice. In stimulating the U3 enhancer, Sox10 synergized with many other Transcription Factors present in neural crest and developing peripheral nervous system including Pax3, FoxD3, AP2α, Krox20 and Sox2. In case of FoxD3, synergism involved Sox10-dependent recruitment to the U3 enhancer, while Sox10 and AP2α each had to bind to the regulatory region. Our study points to the importance of autoregulatory activity and synergistic interactions for maintenance of Sox10 expression and functional activity of Sox10 in the neural crest regulatory network.
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olig2 regulates Sox10 expression in oligodendrocyte precursors through an evolutionary conserved distal enhancer
Nucleic Acids Research, 2011Co-Authors: Melanie Küspert, Michael R Bösl, Alexander Hammer, Michael WegnerAbstract:The HMG-domain Transcription Factor Sox10 is expressed throughout oligodendrocyte development and is an important component of the Transcriptional regulatory network in these myelin-forming CNS glia. Of the known Sox10 regulatory regions, only the evolutionary conserved U2 enhancer in the distal 5′-flank of the Sox10 gene exhibits oligodendroglial activity. We found that U2 was active in oligodendrocyte precursors, but not in mature oligodendrocytes. U2 activity also did not mediate the initial Sox10 induction after specification arguing that Sox10 expression during oligodendroglial development depends on the activity of multiple regulatory regions. The oligodendroglial bHLH Transcription Factor Olig2, but not the closely related Olig1 efficiently activated the U2 enhancer. Olig2 bound U2 directly at several sites including a highly conserved one in the U2 core. Inactivation of this site abolished the oligodendroglial activity of U2 in vivo. In contrast to Olig2, the homeodomain Transcription Factor Nkx6.2 repressed U2 activity. Repression may involve recruitment of Nkx6.2 to U2 and inactivation of Olig2 and other activators by protein–protein interactions. Considering the selective expression of Nkx6.2 at the time of specification and in differentiated oligodendrocytes, Nkx6.2 may be involved in limiting U2 activity to the precursor stage during oligodendrocyte development.
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Sox10 is required for schwann cell identity and progression beyond the immature schwann cell stage
Journal of Cell Biology, 2010Co-Authors: Markus Finzsch, Michael R Bösl, Dies Meijer, Ernst R Tamm, Silke Schreiner, Tatjana I Kichko, Peter W Reeh, Michael WegnerAbstract:Mutations in the Transcription Factor Sox10 cause neurocristopathies, including Waardenburg-Hirschsprung syndrome and peripheral neuropathies in humans. This is partly attributed to a requirement for Sox10 in early neural crest for survival, maintenance of pluripotency, and specification to several cell lineages, including peripheral glia. As a consequence, peripheral glia are absent in Sox10-deficient mice. Intriguingly, Sox10 continues to be expressed in these cells after specification. To analyze glial functions after specification, we specifically deleted Sox10 in immature Schwann cells by conditional mutagenesis. Mutant mice died from peripheral neuropathy before the seventh postnatal week. Nerve alterations included a thinned perineurial sheath, increased lipid and collagen deposition, and a dramatically altered cellular composition. Nerve conduction was also grossly aberrant, and neither myelinating nor nonmyelinating Schwann cells formed. Instead, axons of different sizes remained unsorted in large bundles. Schwann cells failed to develop beyond the immature stage and were unable to maintain identity. Thus, our study identifies a novel cause for peripheral neuropathies in patients with Sox10 mutations.
Hannah Gilmore - One of the best experts on this subject based on the ideXlab platform.
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clinicopathological immunohistochemical and molecular correlation of neural crest Transcription Factor Sox10 expression in triple negative breast carcinoma
Human Pathology, 2018Co-Authors: Aparna Harbhajanka, Satyapal Chahar, Kristy Miskimen, Paula Silverman, Lyndsay Harris, Nicole Williams, Vinay Varadan, Hannah GilmoreAbstract:Summary The Transcription Factor Sox10 mediates the differentiation of neural crest–derived cells, and Sox10 by immunohistochemistry(IHC) is used primarily for the diagnosis of melanoma. Sox10 expression has been previously documented in benign breast myoepithelial cells. However there is limited literature on its expression in triple negative breast carcinoma(TNBC). The aim was to study the clinical, pathologic and molecular profiles of Sox10+ tumors in TNBC. Tissue microarrays of TNBC were evaluated for Sox10 expression in 48cases. Sox10 expression was correlated with clinical and pathologic features such as age, grade, and stage. Gene expression was analyzed on RNA extracted from Formalin fixed paraffin embedded(FFPE) specimens with Affymetrix 2.0 HTA. Co-expression of Sox10 with androgen receptor(AR), WT1, gross cystic disease fluid protein-15(GCDFP-15), mammaglobin, epidermal growth Factor receptor(EGFR), CK5/6 and GATA Transcription Factor 3(GATA3) were also assessed. The mean age was 59.38(range,28–90years). Overall, 37.5% cases(18/48) were Sox10+. There was no association between Sox10 expression and age, grade or stage of patients. 6/10(60%) cases of basal-like 1 (BL1), and 5/8cases of unstable (UNS) molecular subtype were Sox10+. 1/5 basal-like-2 (BL2), 1/6 Immunomodulatory (IM), 1/4 Mesenchymal (M), 1/5 luminal androgen receptor (LAR) and 2/8 Mesenchymal stem cell (MSL) showed lower frequencies of Sox10 expression. There was negative correlation between Sox10 and AR+ subtypes(p-value,
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clinicopathological immunohistochemical and molecular correlation of neural crest Transcription Factor Sox10 expression in triple negative breast carcinoma
Human Pathology, 2018Co-Authors: Aparna Harbhajanka, Satyapal Chahar, Kristy Miskimen, Paula Silverman, Lyndsay Harris, Nicole Williams, Vinay Varadan, Hannah GilmoreAbstract:The Transcription Factor Sox10 mediates the differentiation of neural crest-derived cells, and Sox10 by immunohistochemistry (IHC) is used primarily for the diagnosis of melanoma. Sox10 expression has been previously documented in benign breast myoepithelial cells. However there is limited literature on its expression in triple-negative breast carcinoma (TNBC). The aim was to study the clinical, pathologic and molecular profiles of Sox10+ tumors in TNBC. Tissue microarrays of TNBC were evaluated for Sox10 expression in 48 cases. Sox10 expression was correlated with clinical and pathologic features such as age, grade, and stage. Gene expression was analyzed on RNA extracted from formalin-fixed paraffin-embedded (FFPE) specimens with Affymetrix 2.0 HTA. Co-expression of Sox10 with androgen receptor (AR), WT1, gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, epidermal growth Factor receptor (EGFR), CK5/6 and GATA Transcription Factor 3 (GATA3) were also assessed. The mean age was 59.38 (range, 28-90 years). Overall, 37.5% cases (18/48) were Sox10+. There was no association between Sox10 expression and age, grade or stage of patients; 6 of 10 (60%) cases of basal-like 1 (BL1), and 5 of 8 cases of unstable (UNS) molecular subtype were Sox10+. One of 5 basal-like-2 (BL2), 1 of 6 immunomodulatory (IM), 1 of 4 mesenchymal (M), 1 of 5 luminal androgen receptor (LAR) and 2 of 8 mesenchymal stem cell (MSL) showed lower frequencies of Sox10 expression. There was negative correlation between Sox10 and AR+ subtypes (P < .002). Sox10 was positively correlated with WT1 (P = .05). Sox10 did not show significant correlation with mammaglobin, GCDFP15, EGFR, CK5/6 and GATA3. Sox10 expression in the basal-like and unstable molecular subtypes supports the concept that these neoplasms show myoepithelial differentiation.