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Veronique Lefebvre - One of the best experts on this subject based on the ideXlab platform.
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the transcription factors sox9 and SOX5 sox6 cooperate genome wide through super enhancers to drive chondrogenesis
Nucleic Acids Research, 2015Co-Authors: Chia Feng Liu, Veronique LefebvreAbstract:SOX9 is a transcriptional activator required for chondrogenesis, and SOX5 and SOX6 are closely related DNA-binding proteins that critically enhance its function. We use here genome-wide approaches to gain novel insights into the full spectrum of the target genes and modes of action of this chondrogenic trio. Using the RCS cell line as a faithful model for proliferating/early prehypertrophic growth plate chondrocytes, we uncover that SOX6 and SOX9 bind thousands of genomic sites, frequently and most efficiently near each other. SOX9 recognizes pairs of inverted SOX motifs, whereas SOX6 favors pairs of tandem SOX motifs. The SOX proteins primarily target enhancers. While binding to a small fraction of typical enhancers, they bind multiple sites on almost all super-enhancers (SEs) present in RCS cells. These SEs are predominantly linked to cartilage-specific genes. The SOX proteins effectively work together to activate these SEs and are required for in vivo expression of their associated genes. These genes encode key regulatory factors, including the SOX trio proteins, and all essential cartilage extracellular matrix components. Chst11, Fgfr3, Runx2 and Runx3 are among many other newly identified SOX trio targets. SOX9 and SOX5/SOX6 thus cooperate genome-wide, primarily through SEs, to implement the growth plate chondrocyte differentiation program.
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The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis
Nucleic acids research, 2015Co-Authors: Chia Feng Liu, Veronique LefebvreAbstract:SOX9 is a transcriptional activator required for chondrogenesis, and SOX5 and SOX6 are closely related DNA-binding proteins that critically enhance its function. We use here genome-wide approaches to gain novel insights into the full spectrum of the target genes and modes of action of this chondrogenic trio. Using the RCS cell line as a faithful model for proliferating/early prehypertrophic growth plate chondrocytes, we uncover that SOX6 and SOX9 bind thousands of genomic sites, frequently and most efficiently near each other. SOX9 recognizes pairs of inverted SOX motifs, whereas SOX6 favors pairs of tandem SOX motifs. The SOX proteins primarily target enhancers. While binding to a small fraction of typical enhancers, they bind multiple sites on almost all super-enhancers (SEs) present in RCS cells. These SEs are predominantly linked to cartilage-specific genes. The SOX proteins effectively work together to activate these SEs and are required for in vivo expression of their associated genes. These genes encode key regulatory factors, including the SOX trio proteins, and all essential cartilage extracellular matrix components. Chst11, Fgfr3, Runx2 and Runx3 are among many other newly identified SOX trio targets. SOX9 and SOX5/SOX6 thus cooperate genome-wide, primarily through SEs, to implement the growth plate chondrocyte differentiation program.
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The SOX9 upstream region prone to chromosomal aberrations causing campomelic dysplasia contains multiple cartilage enhancers
Nucleic acids research, 2015Co-Authors: Baojin Yao, Qiuqing Wang, Chia Feng Liu, Pallavi Bhattaram, Timothy J. Mead, James F. Crish, Veronique LefebvreAbstract:Two decades after the discovery that heterozygous mutations within and around SOX9 cause campomelic dysplasia, a generalized skeleton malformation syndrome, it is well established that SOX9 is a master transcription factor in chondrocytes. In contrast, the mechanisms whereby translocations in the –350/–50-kb region 5′ of SOX9 cause severe disease and whereby SOX9 expression is specified in chondrocytes remain scarcely known. We here screen this upstream region and uncover multiple enhancers that activate Sox9-promoter transgenes in the SOX9 expression domain. Three of them are primarily active in chondrocytes. E250 (located at –250 kb) confines its activity to condensed prechondrocytes, E195 mainly targets proliferating chondrocytes, and E84 is potent in all differentiated chondrocytes. E84 and E195 synergize with E70, previously shown to be active in most Sox9-expressing somatic tissues, including cartilage. While SOX9 protein powerfully activates E70, it does not control E250. It requires its SOX5/SOX6 chondrogenic partners to robustly activate E195 and additional factors to activate E84. Altogether, these results indicate that SOX9 expression in chondrocytes relies on widely spread transcriptional modules whose synergistic and overlapping activities are driven by SOX9, SOX5/SOX6 and other factors. They help elucidate mechanisms underlying campomelic dysplasia and will likely help uncover other disease mechanisms.
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Unraveling the transcriptional regulatory machinery in chondrogenesis
Journal of Bone and Mineral Metabolism, 2011Co-Authors: Haruhiko Akiyama, Veronique LefebvreAbstract:Since the discovery of SOX9 mutations in the severe human skeletal malformation syndrome campomelic dysplasia in 1994, Sox9 was shown to be both required and sufficient for chondrocyte specification and differentiation. At the same time, its distant relatives SOX5 and Sox6 were shown to act in redundancy with each other to robustly enhance its functions. The Sox trio is currently best known for its ability to activate the genes for cartilage-specific extracellular matrix components. Sox9 and SOX5/6 homodimerize through domains adjacent to their Sry-related high-mobility-group DNA-binding domain to increase the efficiency of their cooperative binding to chondrocyte-specific enhancers. Sox9 possesses a potent transactivation domain and thereby recruits diverse transcriptional co-activators, histone-modifying enzymes, subunits of the mediator complex, and components of the general transcriptional machinery, such as CBP/p300, Med12, Med25, and Wwp2. This information helps us begin to unravel the mechanisms responsible for Sox9-mediated transcription. We review here the discovery of this master chondrogenic trio and its roles in chondrogenesis in vivo and at the molecular level, and we discuss how these pioneering studies open the way for many additional studies that are needed to further increase our understanding of the transcriptional regulatory machinery operating in chondrogenesis.
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synovial joint morphogenesis requires the chondrogenic action of SOX5 and sox6 in growth plate and articular cartilage
Developmental Biology, 2010Co-Authors: Patrick Smits, Yu Han, Amber Silvester, Alfredo Penzomendez, Bogdan Dumitriu, Carol A De La Motte, David M Kingsley, Veronique LefebvreAbstract:The mechanisms underlying synovial joint development remain poorly understood. Here we use complete and cell-specific gene inactivation to identify the roles of the redundant chondrogenic transcription factors SOX5 and Sox6 in this process. We show that joint development aborts early in complete mutants (SOX5−/−6−/−). Gdf5 and Wnt9a expression is punctual in articular progenitor cells, but Sox9 downregulation and cell condensation in joint interzones are late. Joint cell differentiation is unsuccessful, regardless of lineage, and cavitation fails. SOX5 and Sox6 restricted expression to chondrocytes in wild-type embryos and continued Erg expression and weak Ihh expression in SOX5−/−6−/− growth plates suggest that growth plate failure contribute to this SOX5−/−6−/− joint morphogenesis block. SOX5/6 inactivation in specified joint cells and chondrocytes (SOX5fl/fl6fl/flCol2Cre) also results in a joint morphogenesis block, whereas SOX5/6 inactivation in specified joint cells only (SOX5fl/fl6fl/flGdf5Cre) results in milder joint defects and normal growth plates. SOX5fl/fl6fl/flGdf5Cre articular chondrocytes remain undifferentiated, as shown by continued Gdf5 expression and pancartilaginous gene downregulation. Along with Prg4 downregulation, these defects likely account for joint tissue overgrowth and incomplete cavitation in adult mice. Together, these data suggest that synovial joint morphogenesis relies on essential roles for SOX5/6 in promoting both growth plate and articular chondrocyte differentiation.
Benoit De Crombrugghe - One of the best experts on this subject based on the ideXlab platform.
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sox9 sox6 and sp1 are involved in the insulin like growth factor i mediated upregulation of human type ii collagen gene expression in articular chondrocytes
Journal of Molecular Medicine, 2012Co-Authors: Emmanuelle Renard, Benoit De Crombrugghe, Benoit Poree, Christos Chadjichristos, Magdalini Kypriotou, Laure Maneix, Nicolas Bigot, Florence Legendre, David Ollitrault, Frederic MalleingerinAbstract:Type II collagen is a marker of articular cartilage encoded by the COL2A1 gene. The nature of the trans factors involved in the upregulation of this gene by insulin-like growth factor-I (IGF-I) remains unclear. We found that IGF-I increased type II collagen synthesis by a transcriptional control mechanism involving a 715-bp region within the COL2A1 first-intron specific enhancer. The overproduction of L-SOX5/Sox6/Sox9 and Sp1 and decoy experiments targeting these factors demonstrated their action in concert in IGF-I trans-activation. These results were supported by the data obtained in knockdown experiments in which siRNA against Sox9/Sox6 and Sp1 prevented the IGF-I-induced increase in collagen II production. Indeed, each of these trans-activators increased the expression of others. IGF-I increased the binding of Sox9 and Sp1/Sp3 to their cis elements in the enhancer, and we provide the first evidence of Sox9 interaction with the promoter by chromatin immunoprecipitation. Interactions with COL2A1 were also observed for Sp1, p300/CBP, and Tip60. Finally, a physical interaction between Sox9, p300, Sp3, and Sp1 was detected. These data demonstrate the role of Sox9, Sp1/Sp3, and euchromatin-associated factors (p300, Tip60) in the IGF-I-induced upregulation of COL2A1, indicating possible use of this growth factor in articular cartilage engineering applications to promote repair in patients with degenerative diseases, such as osteoarthritis.
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transcriptional regulation of chondrogenesis by coactivator tip60 via chromatin association with sox9 and SOX5
Nucleic Acids Research, 2008Co-Authors: Takako Hattori, Francoise Coustry, Shelley Stephens, Heidi Eberspaecher, Masaharu Takigawa, Hideyo Yasuda, Benoit De CrombruggheAbstract:Sox9 is a transcription factor of the SRY family required for several steps of chondrogenesis. It activates the expression of various chondrocyte-specific genes, but the mechanisms and role of cofactors involved in Sox9-regulated gene transcription are not fully understood. Here, we report on the characterization of a Tat interactive protein-60 (Tip60) as Sox9-associated protein identified in a yeast two-hybrid screen. Both in vitro and in vivo assays confirmed the specificity of interactions between Sox9 and Tip60 including the existence of an endogenous complex containing both polypeptides in chondrocytes. Gel shift assays showed the presence of a complex containing Sox9, Tip60 and the DNA of an enhancer region of the Col2a1 promoter. Reporter assays using a Col2a1 promoter with multimerized Col2a1 Sox9-binding sites indicated that Tip60 enhanced the transcriptional activity of Sox9. A larger Col2a1 promoter showed that Tip60 increased the activity of this promoter in the presence of both Sox9 and SOX5. Ectopic expression of Sox9 and transient-cotransfection with Tip60 in COS7 cells showed a more diffuse subnuclear colocalization, suggesting changes in the chromatin structure. Chromatin immunoprecipitation assays showed that Tip60, Sox9 and SOX5 associated with the same Col2a1 enhancer region. Consistent with a role of Tip60 in chondrogenesis, addition of Tip60 siRNA to limb-bud micromass cultures delayed chondrocyte differention. Tip60 enhances acetylation of Sox9 mainly through K61, 253, 398 residues; however, the K61/253/398A mutant of Sox9 still exhibited enhanced transcriptional activity by Tip60. Our results support the hypothesis that Tip60 is a coactivator of Sox9 in chondrocytes.
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Misexpression of Sox9 in mouse limb bud mesenchyme induces polydactyly and rescues hypodactyly mice
Matrix biology : journal of the International Society for Matrix Biology, 2006Co-Authors: Haruhiko Akiyama, James F Martin, H. Scott Stadler, Takahiro Ishii, Philip A. Beachy, Takashi Nakamura, Benoit De CrombruggheAbstract:Our previous studies have demonstrated the essential roles of the transcription factor Sox9 in the commitment of mesenchymal cells to a chondrogenic cell lineage and in overt chondrogenesis during limb bud development. However, it remains unknown if Sox9 induces chondrogenesis in mesenchyme ectopically in vivo as a master regulator of chondrogenesis. In this study, we first generated mutant mice in which Sox9 was misexpressed in the limb bud mesenchyme. The mutant mouse embryos exhibited polydactyly in limb buds in association with ectopic expression of SOX5 and Sox6 although markers for the different axes of limb bud development showed a normal pattern of expression. Misexpression of Sox9 stimulated cell proliferation in limb bud mesenchyme, suggesting that Sox9 has a role in recruiting mesenchymal cells to mesenchymal condensation. Second, despite the facts that misexpression of Sonic hedgehog (Shh) induces polydactyly in a number of mutant mice and Shh-null mutants have severely defective cartilage elements in limb buds, misexpression of Sox9 did not restore limb bud phenotypes in Shh-null mutants. Rather, there was no expression of Sox9 in digit I of Hoxa13Hd mutant embryos, and Sox9 partially rescued hypodactyly in Hoxa13Hd mutant embryos. These results provide evidence that Sox9 induces ectopic chondrogenesis in mesenchymal cells and strongly suggest that its expression may be regulated by Hox genes during limb bud development.
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the transcription factor sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of SOX5 and sox6
Genes & Development, 2002Co-Authors: Haruhiko Akiyama, Marie-christine Chaboissier, Andreas Schedl, James F Martin, Benoit De CrombruggheAbstract:To examine whether the transcription factor Sox9 has an essential role during the sequential steps of chondrocyte differentiation, we have used the Cre/loxP recombination system to generate mouse embryos in which either Sox9 is missing from undifferentiated mesenchymal cells of limb buds or the Sox9 gene is inactivated after chondrogenic mesenchymal condensations. Inactivation of Sox9 in limb buds before mesenchymal condensations resulted in a complete absence of both cartilage and bone, but markers for the different axes of limb development showed a normal pattern of expression. Apoptotic domains within the developing limbs were expanded, suggesting that Sox9 suppresses apoptosis. Expression of SOX5 and Sox6, two other Sox genes involved in chondrogenesis, was no longer detected. Moreover, expression of Runx2, a transcription factor needed for osteoblast differentiation, was also abolished. Embryos, in which Sox9 was deleted after mesenchymal condensations, exhibited a severe generalized chondrodysplasia, similar to that in SOX5; Sox6 double-null mutant mice. Most cells were arrested as condensed mesenchymal cells and did not undergo overt differentiation into chondrocytes. Furthermore, chondrocyte proliferation was severely inhibited and joint formation was defective. Although Indian hedgehog, Patched1, parathyroid hormone-related peptide (Pthrp), and Pth/Pthrp receptor were expressed, their expression was down-regulated. Our experiments further suggested that Sox9 is also needed to prevent conversion of proliferating chondrocytes into hypertrophic chondrocytes. We conclude that Sox9 is required during sequential steps of the chondrocyte differentiation pathway.
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the transcription factors l SOX5 and sox6 are essential for cartilage formation
Developmental Cell, 2001Co-Authors: Patrick Smits, Richard R Behringer, Jennifer Mandel, Zhaoping Zhang, Jian Ming Deng, Benoit De Crombrugghe, Ping Li, Veronique LefebvreAbstract:Abstract L-SOX5 and Sox6 are highly identical Sry-related transcription factors coexpressed in cartilage. Whereas SOX5 and Sox6 single null mice are born with mild skeletal abnormalities, SOX5; Sox6 double null fetuses die with a severe, generalized chondrodysplasia. In these double mutants, chondroblasts poorly differentiate. They express the genes for all essential cartilage extracellular matrix components at low or undetectable levels and initiate proliferation after a long delay. All cartilages are thus extracellular matrix deficient and remain rudimentary. While chondroblasts in the center of cartilages ultimately activate prehypertrophic chondrocyte markers, epiphyseal chondroblasts ectopically activate hypertrophic chondrocyte markers. Thick intramembranous bone collars develop, but the formation of cartilage growth plates and endochondral bones is disrupted. L-SOX5 and Sox6 are thus redundant, potent enhancers of chondroblast functions, thereby essential for endochondral skeleton formation.
Michael Wegner - One of the best experts on this subject based on the ideXlab platform.
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transcription factors SOX5 and sox6 exert direct and indirect influences on oligodendroglial migration in spinal cord and forebrain
Glia, 2016Co-Authors: Tina Baroti, Michael Wegner, Yvonne Zimmermann, Anja Schillinger, Lina Liu, Petra Lommes, Claus C StoltAbstract:Transcription factors of the SoxD protein family have previously been shown to prevent precocious specification and terminal differentiation of oligodendrocyte progenitor cells in the developing spinal cord. Using mice with specific deletion of the SoxD proteins SOX5 and Sox6 in the central nervous system, we now show that SoxD proteins additionally influence migration of oligodendrocyte progenitors in the spinal cord as well as in the forebrain. In mutant mice, emigration of oligodendrocyte progenitors from the ventricular zone and colonization of the mantle zone are significantly delayed probably because of reduced expression of Pdgf receptor alpha and decreased responsiveness toward Pdgf-A as a main migratory cue. In addition to this direct cell-autonomous effect on Pdgf receptor alpha expression, SoxD proteins furthermore promote oligodendroglial migration by keeping the cells in an undifferentiated state and preventing a premature loss of their migratory capacity. This indirect effect becomes particularly important during late embryonic and early postnatal phases of oligodendroglial development. Finally, we show that SOX5 and Sox6 cooperate with Sox9 and Sox10 to activate Pdgf receptor alpha expression and thereby maintain oligodendrocyte progenitors in the immature state. This contrasts with their behavior on myelin genes where they antagonize the function of SoxE proteins. It argues that SoxD proteins can function either as repressors or as co-activators of SoxE proteins thereby modulating their function in a stage-specific manner.
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Sox13 functionally complements the related SOX5 and Sox6 as important developmental modulators in mouse spinal cord oligodendrocytes.
Journal of neurochemistry, 2015Co-Authors: Tina Baroti, Michael Wegner, Anja Schillinger, Claus C StoltAbstract:The role of transcription factor Sox13, which together with SOX5 and Sox6 belongs to the SoxD family, is only poorly characterized in central nervous system development. Therefore, we analysed whether Sox13 expression and function overlaps with or differs from that of its close relatives SOX5 and Sox6. In the developing mouse spinal cord, we found Sox13 predominantly expressed in neuroepithelial precursors, oligodendroglial and astroglial cells. The substantially overlapping expression with SOX5 and Sox6 in oligodendroglial cells prompted us to study potential roles during specification, lineage progression and differentiation of oligodendrocytes. In contrast to SOX5 and Sox6, Sox13 expression continues after differentiation and even increases in myelinating oligodendrocytes. Sox13 deletion did not interfere with oligodendroglial development, which was normal in Sox13-deficient mice. However, the premature differentiation of oligodendrocyte precursors triggered by loss of Sox6 was slightly more prominent in Sox6/Sox13 double-deficient mice. Sox13 can bind to the same sites in myelin gene promoters as SOX5 and Sox6 in vitro. Reporter gene assays furthermore reveal a similar antagonizing effect on Sox10-dependent transactivation of myelin gene promoters as previously shown for SOX5 and Sox6. This argues that Sox13 is functionally redundant with the other SoxD proteins and complements SOX5 and Sox6 in their role as important modulators of oligodendrocyte development. The transcription factor Sox13 is co-expressed with the related SOX5 and Sox6 in cells of the oligodendroglial lineage. By itself, it has little impact on oligodendrocyte development but supports SOX5 and Sox6 during the process as a functionally redundant transcription factor.
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SOX5 controls dorsal progenitor and interneuron specification in the spinal cord
Developmental neurobiology, 2014Co-Authors: Alejandra C. Quiroga, Michael Wegner, C. Claus Stolt, Ruth Diez Del Corral, Spas Dimitrov, Siro Perez-alcala, Elisabeth Sock, Julio A. Barbas, Aixa V. MoralesAbstract:The basic organization of somatosensory circuits in the spinal cord is already setup during the initial patterning of the dorsal neural tube. Extrinsic signals, such as Wnt and TGF-β pathways, activate combinatorial codes of transcription factors that are responsible for generating a pattern of discrete domains of dorsal progenitors (dp). These progenitors will give rise to distinct dorsal interneurons (dI). The Wnt/ βcatenin signaling pathway controls specification of dp/dI1–3 progenitors and interneurons. According to the current model in the field, Wnt/βcatenin activity seems to act in a graded fashion in the spinal cord, as different relative levels determine the identity of adjacent progenitors. However, it is not clear how this activity gradient is controlled and how the identities of dI1–3 are differentially regulated by Wnt signalling. We have determined that two SoxD transcription factors, SOX5 and Sox6, are expressed in restricted domains of dorsal progenitors in the neural tube. Using gain- and loss-of function approaches in chicken embryos, we have established that SOX5 controls cell fate specification of dp2 and dp3 progenitors and, as a result, controls the correct number of the corresponding dorsal interneurons (dI2 and dI3). Furthermore, SOX5 exerts its function by restricting dorsally Wnt signaling activity via direct transcriptional induction of the negative Wnt pathway regulator Axin2. By that way, SOX5 acts as a Wnt pathway modulator that contributes to sharpen the dorsal gradient of Wnt/βcatenin activity to control the distinction of two functionally distinct types of interneurons, dI2 and dI3 involved in the somatosensory relay. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 522–538, 2015
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soxe function in vertebrate nervous system development
The International Journal of Biochemistry & Cell Biology, 2010Co-Authors: Claus C Stolt, Michael WegnerAbstract:Sox8, Sox9, and Sox10 as transcription factors of subgroup E of the Sox protein family are essential for many aspects of nervous system development. These SoxE proteins are already required for the initial neural crest induction, but also guarantee survival and maintenance of pluripotency in migrating neural crest stem cells. SoxE proteins are furthermore key regulators of glial specification in both the peripheral and the central nervous systems. At later stages of development, Sox10 plays crucial roles in Schwann cells and oligodendrocytes for terminal differentiation and myelin formation. In both glial cell types, Sox10 controls directly the expression of genes encoding the major myelin proteins. SoxE proteins are well-integrated components of regulatory networks and as such modulated in their activity by cooperating or antagonistic transcription factors such as SoxD or various bHLH proteins. The multiple functions in peripheral and central nervous system development also link SoxE proteins to various human diseases and identify these proteins as promising targets of future therapeutic approaches.
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Testis cord differentiation after the sex determination stage is independent of Sox9 but fails in the combined absence of Sox9 and Sox8
Developmental Biology, 2009Co-Authors: F. Barrionuevo, Michael Wegner, Ina Georg, Harry Scherthan, Charlotte Lécureuil, Florian Jean Louis Guillou, Gerd SchererAbstract:Sox9 and Sox8 are transcription factors expressed in embryonic and postnatal Sertoli cells of the mouse testis. Sox9 inactivation prior to the sex determination stage leads to complete XY sex reversal. In contrast, there is normal embryonic testis development in Sox8 mutants which are initially fertile, but later develop progressive seminiferous tubule failure and infertility. To determine whether Sox9 is required for testis development after the initial steps of sex determination, we crossed Sox9(flox) mice with an AMH-Cre transgenic line thereby completely deleting Sox9 in Sertoli cells by E14.0. Conditional Sox9 null mutants show normal embryonic testis development and are initially fertile, but, like Sox8(-1-) mutants, become sterile from dysfunctional spermatogenesis at about 5 months. To see whether Sox8 may compensate for the absence of Sox9 during embryonic testis differentiation, we generated a Sox9 conditional knockout on a Sox8 mutant background. In the double mutants, differentiation of testis cords into seminiferous testis tubules ceases after P6 in the absence of one Sox8 allele, and after PO in the absence of both Sox8 alleles, leading to complete primary infertility. Sox9,Sox8 double nullizygous testes show upregulation of early ovary-specific markers and downregulation of Sertoli intercellular junctions at E15.5. Their very low Amh levels still cause complete regression of the Mullerian duct but with reduced penetrance. This study shows that testis cord differentiation is independent of Sox9, and that concerted Sox9 and Sox8 function in post E14.0 Sertoli cells is essential for the maintenance of testicular function. (C) 2008 Elsevier Inc. All rights reserved.
Claus C Stolt - One of the best experts on this subject based on the ideXlab platform.
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transcription factors SOX5 and sox6 exert direct and indirect influences on oligodendroglial migration in spinal cord and forebrain
Glia, 2016Co-Authors: Tina Baroti, Michael Wegner, Yvonne Zimmermann, Anja Schillinger, Lina Liu, Petra Lommes, Claus C StoltAbstract:Transcription factors of the SoxD protein family have previously been shown to prevent precocious specification and terminal differentiation of oligodendrocyte progenitor cells in the developing spinal cord. Using mice with specific deletion of the SoxD proteins SOX5 and Sox6 in the central nervous system, we now show that SoxD proteins additionally influence migration of oligodendrocyte progenitors in the spinal cord as well as in the forebrain. In mutant mice, emigration of oligodendrocyte progenitors from the ventricular zone and colonization of the mantle zone are significantly delayed probably because of reduced expression of Pdgf receptor alpha and decreased responsiveness toward Pdgf-A as a main migratory cue. In addition to this direct cell-autonomous effect on Pdgf receptor alpha expression, SoxD proteins furthermore promote oligodendroglial migration by keeping the cells in an undifferentiated state and preventing a premature loss of their migratory capacity. This indirect effect becomes particularly important during late embryonic and early postnatal phases of oligodendroglial development. Finally, we show that SOX5 and Sox6 cooperate with Sox9 and Sox10 to activate Pdgf receptor alpha expression and thereby maintain oligodendrocyte progenitors in the immature state. This contrasts with their behavior on myelin genes where they antagonize the function of SoxE proteins. It argues that SoxD proteins can function either as repressors or as co-activators of SoxE proteins thereby modulating their function in a stage-specific manner.
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Sox13 functionally complements the related SOX5 and Sox6 as important developmental modulators in mouse spinal cord oligodendrocytes.
Journal of neurochemistry, 2015Co-Authors: Tina Baroti, Michael Wegner, Anja Schillinger, Claus C StoltAbstract:The role of transcription factor Sox13, which together with SOX5 and Sox6 belongs to the SoxD family, is only poorly characterized in central nervous system development. Therefore, we analysed whether Sox13 expression and function overlaps with or differs from that of its close relatives SOX5 and Sox6. In the developing mouse spinal cord, we found Sox13 predominantly expressed in neuroepithelial precursors, oligodendroglial and astroglial cells. The substantially overlapping expression with SOX5 and Sox6 in oligodendroglial cells prompted us to study potential roles during specification, lineage progression and differentiation of oligodendrocytes. In contrast to SOX5 and Sox6, Sox13 expression continues after differentiation and even increases in myelinating oligodendrocytes. Sox13 deletion did not interfere with oligodendroglial development, which was normal in Sox13-deficient mice. However, the premature differentiation of oligodendrocyte precursors triggered by loss of Sox6 was slightly more prominent in Sox6/Sox13 double-deficient mice. Sox13 can bind to the same sites in myelin gene promoters as SOX5 and Sox6 in vitro. Reporter gene assays furthermore reveal a similar antagonizing effect on Sox10-dependent transactivation of myelin gene promoters as previously shown for SOX5 and Sox6. This argues that Sox13 is functionally redundant with the other SoxD proteins and complements SOX5 and Sox6 in their role as important modulators of oligodendrocyte development. The transcription factor Sox13 is co-expressed with the related SOX5 and Sox6 in cells of the oligodendroglial lineage. By itself, it has little impact on oligodendrocyte development but supports SOX5 and Sox6 during the process as a functionally redundant transcription factor.
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soxe function in vertebrate nervous system development
The International Journal of Biochemistry & Cell Biology, 2010Co-Authors: Claus C Stolt, Michael WegnerAbstract:Sox8, Sox9, and Sox10 as transcription factors of subgroup E of the Sox protein family are essential for many aspects of nervous system development. These SoxE proteins are already required for the initial neural crest induction, but also guarantee survival and maintenance of pluripotency in migrating neural crest stem cells. SoxE proteins are furthermore key regulators of glial specification in both the peripheral and the central nervous systems. At later stages of development, Sox10 plays crucial roles in Schwann cells and oligodendrocytes for terminal differentiation and myelin formation. In both glial cell types, Sox10 controls directly the expression of genes encoding the major myelin proteins. SoxE proteins are well-integrated components of regulatory networks and as such modulated in their activity by cooperating or antagonistic transcription factors such as SoxD or various bHLH proteins. The multiple functions in peripheral and central nervous system development also link SoxE proteins to various human diseases and identify these proteins as promising targets of future therapeutic approaches.
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from stem cells to neurons and glia a soxist s view of neural development
Trends in Neurosciences, 2005Co-Authors: Michael Wegner, Claus C StoltAbstract:During nervous system development, neural stem cells give rise to many different types of neurons and glia over an extended period. Little is known about the intrinsic factors that regulate stem-cell maintenance, decide whether neurons or glia are generated, or control terminal differentiation. Transcription factors of the Sox family provide important clues about the control of these events. In the central nervous system (CNS), Sox1, Sox2 and Sox3 are required for stem-cell maintenance, and their effects are counteracted by Sox21. Sox9, by contrast, alters the potential of stem cells from neurogenic to gliogenic, whereas Sox10 is essential for terminal oligodendrocyte differentiation. In the peripheral nervous system (PNS) the same Sox proteins have different functions, uncovering important developmental differences between the CNS and PNS.
Gerd Scherer - One of the best experts on this subject based on the ideXlab platform.
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l SOX5 and sox6 proteins enhance chondrogenic mir 140 microrna expression by strengthening dimeric sox9 activity
Journal of Biological Chemistry, 2012Co-Authors: Satoshi Yamashita, Haruhiko Akiyama, Gerd Scherer, Shigeru Miyaki, Yoshio Kato, Shigetoshi Yokoyama, Tempei Sato, Francisco J Barrionuevo, Shuji Takada, Hiroshi AsaharaAbstract:Sox9 plays a critical role in early chondrocyte initiation and promotion as well as repression of later maturation. Fellow Sox family members L-SOX5 and Sox6 also function as regulators of cartilage development by boosting Sox9 activation of chondrocyte-specific genes such as Col2a1 and Agc1; however, the regulatory mechanism and other target genes are largely unknown. MicroRNAs are a class of short, non-coding RNAs that act as negative regulators of gene expression by promoting target mRNA degradation and/or repressing translation. Analysis of genetically modified mice identified miR-140 as a cartilage-specific microRNA that could be a critical regulator of cartilage development and homeostasis. Recent findings suggest Sox9 promotes miR-140 expression, although the detailed mechanisms are not fully understood. In this study we demonstrate that the proximal upstream region of pri-miR-140 has chondrogenic promoter activity in vivo. We found an L-SOX5/Sox6/Sox9 (Sox trio) response element and detailed binding site in the promoter region. Furthermore, detailed analysis suggests the DNA binding and/or transactivation ability of Sox9 as a homodimer is boosted by L-SOX5 and Sox6. These findings provide new insight into cartilage-specific gene regulation by the Sox trio.
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SOX E genes: SOX9 and SOX8 in mammalian testis development.
The international journal of biochemistry & cell biology, 2009Co-Authors: Francisco J Barrionuevo, Gerd SchererAbstract:The group E SOX proteins consist of SOX8, SOX9 and SOX10. These transcription factors contain, besides a DNA-binding HMG domain and a transactivation domain, a DNA-dependent dimerization domain, unique among SOX proteins. Among these three SOX E proteins, which are all expressed during mammalian testis development, SOX9 stands out in importance. It is SOX9 that becomes activated by SRY in pre-Sertoli cells, executing SRY's role as a testis-determining factor by inducing Sertoli cell and testis cord differentiation. However, Sox9 is dispensable during subsequent embryonic and postnatal testis development, since ablation of Sox9 at embryonic day 14.0, after the sex determination stage, only leads to late-onset sterility at about 5 months. A similar late male sterility phenotype occurs in constitutive Sox8 null mutants. In the combined absence of Sox9 and Sox8, primary male infertility evolves, revealing functional redundancy. Loss of Sox10 has no effect on testis development.
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Testis cord differentiation after the sex determination stage is independent of Sox9 but fails in the combined absence of Sox9 and Sox8
Developmental Biology, 2009Co-Authors: F. Barrionuevo, Michael Wegner, Ina Georg, Harry Scherthan, Charlotte Lécureuil, Florian Jean Louis Guillou, Gerd SchererAbstract:Sox9 and Sox8 are transcription factors expressed in embryonic and postnatal Sertoli cells of the mouse testis. Sox9 inactivation prior to the sex determination stage leads to complete XY sex reversal. In contrast, there is normal embryonic testis development in Sox8 mutants which are initially fertile, but later develop progressive seminiferous tubule failure and infertility. To determine whether Sox9 is required for testis development after the initial steps of sex determination, we crossed Sox9(flox) mice with an AMH-Cre transgenic line thereby completely deleting Sox9 in Sertoli cells by E14.0. Conditional Sox9 null mutants show normal embryonic testis development and are initially fertile, but, like Sox8(-1-) mutants, become sterile from dysfunctional spermatogenesis at about 5 months. To see whether Sox8 may compensate for the absence of Sox9 during embryonic testis differentiation, we generated a Sox9 conditional knockout on a Sox8 mutant background. In the double mutants, differentiation of testis cords into seminiferous testis tubules ceases after P6 in the absence of one Sox8 allele, and after PO in the absence of both Sox8 alleles, leading to complete primary infertility. Sox9,Sox8 double nullizygous testes show upregulation of early ovary-specific markers and downregulation of Sertoli intercellular junctions at E15.5. Their very low Amh levels still cause complete regression of the Mullerian duct but with reduced penetrance. This study shows that testis cord differentiation is independent of Sox9, and that concerted Sox9 and Sox8 function in post E14.0 Sertoli cells is essential for the maintenance of testicular function. (C) 2008 Elsevier Inc. All rights reserved.
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Testis cord differentiation after the sex determination stage is independent of Sox9 but fails in the combined absence of Sox9 and Sox8
Developmental biology, 2008Co-Authors: Francisco J Barrionuevo, Michael Wegner, Ina Georg, Harry Scherthan, Charlotte Lécureuil, Florian Guillou, Gerd SchererAbstract:Sox9 and Sox8 are transcription factors expressed in embryonic and postnatal Sertoli cells of the mouse testis. Sox9 inactivation prior to the sex determination stage leads to complete XY sex reversal. In contrast, there is normal embryonic testis development in Sox8 mutants which are initially fertile, but later develop progressive seminiferous tubule failure and infertility. To determine whether Sox9 is required for testis development after the initial steps of sex determination, we crossed Sox9(flox) mice with an AMH-Cre transgenic line thereby completely deleting Sox9 in Sertoli cells by E14.0. Conditional Sox9 null mutants show normal embryonic testis development and are initially fertile, but, like Sox8(-/-) mutants, become sterile from dysfunctional spermatogenesis at about 5 months. To see whether Sox8 may compensate for the absence of Sox9 during embryonic testis differentiation, we generated a Sox9 conditional knockout on a Sox8 mutant background. In the double mutants, differentiation of testis cords into seminiferous testis tubules ceases after P6 in the absence of one Sox8 allele, and after P0 in the absence of both Sox8 alleles, leading to complete primary infertility. Sox9,Sox8 double nullizygous testes show upregulation of early ovary-specific markers and downregulation of Sertoli intercellular junctions at E15.5. Their very low Amh levels still cause complete regression of the Mullerian duct but with reduced penetrance. This study shows that testis cord differentiation is independent of Sox9, and that concerted Sox9 and Sox8 function in post E14.0 Sertoli cells is essential for the maintenance of testicular function.
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Loss of Sox9 function results in defective chondrocyte differentiation of mouse embryonic stem cells in vitro.
The International Journal of Developmental Biology, 2008Co-Authors: Gunnar Hargus, Ralf Kist, Gerd Scherer, Jan Kramer, Daniela Gerstel, Angela Neitz, Jürgen RohwedelAbstract:The transcription factor Sox9 plays an important role during chondrogenesis. After early conditional inactivation of Sox9 in mesenchymal limb bud cells of mice, mesenchymal condensations as well as cartilage and bone are completely absent in the developing limbs. We analyzed chondrogenic differentiation of Sox9-/- mouse embryonic stem cells in vitro, using two clones with different targeted mutations. We found that the development of mature and hypertrophic chondrocytes is completely inhibited in the absence of Sox9 confirming that Sox9 is required for the formation of cartilage. In contrast, Sox9+/- mouse embryonic stem cells showed continous but reduced differentiation into mature chondrocytes. Interestingly, the formation of early chondrogenic condensations expressing characteristic marker genes such as scleraxis, SOX5 and Sox6 was not inhibited in the absence of Sox9 in vitro. Thus, we propose that the earliest step of chondrogenesis could be regulated by a non cell-autonomous function of Sox9.