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Véronique 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, Véronique 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, Véronique 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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Unraveling the transcriptional regulatory machinery in chondrogenesis
Journal of Bone and Mineral Metabolism, 2011Co-Authors: Haruhiko Akiyama, Véronique 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, Véronique 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.
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the soxd transcription factors sox5 sox6 and sox13 are key cell fate modulators
The International Journal of Biochemistry & Cell Biology, 2010Co-Authors: Véronique LefebvreAbstract:Sox5, Sox6, and Sox13 constitute the group D of sex-determining region (Sry)-related transcription factors. They are highly conserved in the family-specific high-mobility-group (HMG) box DNA-binding domain and in a group-specific coiled-coil domain. The latter mediates SoxD protein dimerization and thereby preferential binding to pairs of DNA recognition sites. The SoxD genes have overlapping expression and cell-autonomously control discrete lineages. Sox5 and Sox6 redundantly enhance chondrogenesis, but retard gliogenesis. Sox5 hinders melanogenesis, promotes neural crest generation, and controls the pace of neurogenesis. Sox6 promotes erythropoiesis, and Sox13 modulates T cell specification and is an autoimmune antigen. SoxD proteins enhance transactivation by SOX9 in chondrocytes, but antagonize SOX9 and other SoxE proteins in oligodendrocytes and melanocytes, and also repress transcription through various mechanisms in several other lineages. While their biological and molecular functions remain incompletely understood, the SoxD proteins have thus already proven that they critically modulate cell fate in major lineages.
Michael Wegner - One of the best experts on this subject based on the ideXlab platform.
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Transcription factor profiling identifies SOX9 as regulator of proliferation and differentiation in corneal epithelial stem/progenitor cells
Scientific Reports, 2018Co-Authors: Johannes Menzel-severing, Michael Wegner, Matthias Zenkel, Naresh Polisetti, Elisabeth Sock, Friedrich E. Kruse, Ursula Schlötzer-schrehardtAbstract:Understanding transcription factor (TF) regulation of limbal epithelial stem/progenitor cells (LEPCs) may aid in using non-ocular cells to regenerate the corneal surface. This study aimed to identify and characterize TF genes expressed specifically in LEPCs isolated from human donor eyes by laser capture microdissection. Using a profiling approach, preferential limbal expression was found for SoxE and SoxF genes, particularly for SOX9, which showed predominantly cytoplasmic localization in basal LEPCs and nuclear localization in suprabasal and corneal epithelial cells, indicating nucleocytoplasmic translocation and activation during LEPC proliferation and differentiation. Increased nuclear localization of SOX9 was also observed in activated LEPCs following clonal expansion and corneal epithelial wound healing. Knockdown of SOX9 expression in cultured LEPCs by RNAi led to reduced expression of progenitor cell markers, e.g. keratin 15, and increased expression of differentiation markers, e.g. keratin 3. Furthermore, SOX9 silencing significantly suppressed the proliferative capacity of LEPCs and reduced levels of glycogen synthase kinase 3 beta (GSK-3ß), a negative regulator of Wnt/ß-catenin signaling. SOX9 expression, in turn, was significantly suppressed by treatment of LEPCs with exogenous GSK-3ß inhibitors and enhanced by small molecule inhibitors of Wnt signaling. Our results suggest that SOX9 and Wnt/ß-catenin signaling cooperate in mutually repressive interactions to achieve a balance between quiescence, proliferation and differentiation of LEPCs in the limbal niche. Future molecular dissection of SOX9-Wnt interaction and mechanisms of nucleocytoplasmic shuttling of SOX9 may aid in improving the regenerative potential of LEPCs and the reprogramming of non-ocular cells for corneal surface regeneration.
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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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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.
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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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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L-Sox5, Sox6 and SOX9 control essential steps of the chondrocyte differentiation pathway.
Osteoarthritis and Cartilage, 2001Co-Authors: Véronique Lefebvre, Richard R. Behringer, Benoit De CrombruggheAbstract:Abstract Objective This work was carried out to identify transcription factors controlling the differentiation of mesenchymal cells into chondrocytes. Design We delineated a cartilage-specific enhancer in the collagen type 2 gene (Col2a1) and identified transcription factors responsible for the activity of this enhancer in chondrocytes. We then analyzed the ability of these transcription factors to activate specific genes of the chondrocyte differentiation program and control cartilage formation in vivo . Results A 48-bp sequence in the first intron of Col2a1 drove gene expression specifically in cartilage in transgenic mouse embryos. The transcription factors L-Sox5, Sox6, and SOX9 bound and cooperatively activated this enhancer in vitro. They belong to the Sry-related family of HMG box DNA-binding proteins, which includes many members implicated in cell fate determination in various lineages. L-Sox5, Sox6, and SOX9 were coexpressed in all precartilaginous condensations in mouse embryos and continued to be expressed in chondrocytes until the cells underwent final hypertrophy. Whereas L-Sox5 and Sox6 are highly homologous proteins, they are totally different from SOX9 outside the HMG box domain. The three proteins cooperatively activated the Col2a1- and aggrecan genes in cultured cells. Heterozygous mutations in SOX9 in humans lead to campomelic dysplasia, a severe and generalized skeletal malformation syndrome. Embryonic cells with a homozygous SOX9 mutation were unable to form cartilage in vivo and activate essential chondrocyte marker genes. Preliminary data indicated that the mutation of Sox5 and Sox6 in the mouse led to severe skeletal malformations. Conclusions L-Sox5, Sox6, and SOX9 play essential roles in chondrocyte differentiation and, thereby, in cartilage formation. Their discovery will help to understand further the molecular mechanisms controlling chondrogenesis in vivo , uncover genetic mechanisms underlying cartilage diseases, and develop novel strategies for cartilage repair.
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L-Sox5, Sox6 and SOX9 control essential steps of the chondrocyte differentiation pathway.
Osteoarthritis and cartilage, 2001Co-Authors: V Lefebvre, Richard R. Behringer, Benoit De CrombruggheAbstract:This work was carried out to identify transcription factors controlling the differentiation of mesenchymal cells into chondrocytes. We delineated a cartilage-specific enhancer in the collagen type 2 gene (Col2a1) and identified transcription factors responsible for the activity of this enhancer in chondrocytes. We then analyzed the ability of these transcription factors to activate specific genes of the chondrocyte differentiation program and control cartilage formation in vivo. A 48-bp sequence in the first intron of Col2a1 drove gene expression specifically in cartilage in transgenic mouse embryos. The transcription factors L-Sox5, Sox6, and SOX9 bound and cooperatively activated this enhancer in vitro. They belong to the Sry-related family of HMG box DNA-binding proteins, which includes many members implicated in cell fate determination in various lineages. L-Sox5, Sox6, and SOX9 were coexpressed in all precartilaginous condensations in mouse embryos and continued to be expressed in chondrocytes until the cells underwent final hypertrophy. Whereas L-Sox5 and Sox6 are highly homologous proteins, they are totally different from SOX9 outside the HMG box domain. The three proteins cooperatively activated the Col2a1- and aggrecan genes in cultured cells. Heterozygous mutations in SOX9 in humans lead to campomelic dysplasia, a severe and generalized skeletal malformation syndrome. Embryonic cells with a homozygous SOX9 mutation were unable to form cartilage in vivo and activate essential chondrocyte marker genes. Preliminary data indicated that the mutation of Sox5 and Sox6 in the mouse led to severe skeletal malformations. L-Sox5, Sox6, and SOX9 play essential roles in chondrocyte differentiation and, thereby, in cartilage formation. Their discovery will help to understand further the molecular mechanisms controlling chondrogenesis in vivo, uncover genetic mechanisms underlying cartilage diseases, and develop novel strategies for cartilage repair.
Marie-christine Chaboissier - One of the best experts on this subject based on the ideXlab platform.
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Sox8 and SOX9 act redundantly for ovarian-to-testicular fate reprogramming in the absence of R-spondin1 in mouse sex reversals
eLife, 2020Co-Authors: Nainoa Richardson, Isabelle Gillot, Elodie Grégoire, Sameh Youssef, Dirk De Rooij, Alain De Bruin, Marie-cécile De Cian, Marie-christine ChaboissierAbstract:In mammals, testicular differentiation is initiated by transcription factors SRY and SOX9 in XY gonads, and ovarian differentiation involves R-spondin1 (RSPO1) mediated activation of WNT/β-catenin signaling in XX gonads. Accordingly, the absence of RSPO1/Rspo1 in XX humans and mice leads to testicular differentiation and female-to-male sex reversal in a manner that does not requireSry or SOX9 in mice. Here we show that an alternate testis-differentiating factor exists and that this factor is Sox8. Specifically, genetic ablation of Sox8 and SOX9 prevents ovarian-to-testicular reprogramming observed in XX Rspo1 loss-of-function mice. Consequently, Rspo1 Sox8 SOX9 triple mutant gonads developed as atrophied ovaries. Thus, SOX8 alone can compensate for the loss of SOX9 for Sertoli cell differentiation during female-to-male sex reversal.
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sox8 and SOX9 act redundantly for ovarian to testicular fate reprogramming in the absence of rspo1 in mouse sex reversal
bioRxiv, 2019Co-Authors: Marie-christine Chaboissier, Nainoa Richardson, Elodie P. Gregoire, Dirk G. De Rooij, Isabelle Gillot, Alain De Bruin, Sameh A Youssef, Marie-cécile De CianAbstract:In mammals, testicular differentiation is initiated by transcription factors SRY and SOX9 in XY gonads, and ovarian differentiation involves R-spondin1 (RSPO1) mediated activation of WNT/β-catenin signaling in XX gonads. Accordingly, the absence of RSPO1/Rspo1 in XX humans and mice leads to testicular differentiation and female-to-male sex reversal in a manner that does not require Sry or SOX9 in mice. Here we show that an alternate testis-differentiating factor exists and that this factor is Sox8. Specifically, genetic ablation of Sox8 and SOX9 prevents ovarian-to testicular reprogramming observed in XX Rspo1 loss-of-function mice. Consequently, Rspo1 Sox8 SOX9 triple mutant gonads developed as atrophied ovaries. Thus, SOX8 alone can compensate for the loss of SOX9 for Sertoli cell differentiation during female-to-male sex reversal.
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Testicular Differentiation Occurs in Absence of R-spondin1 and SOX9 in Mouse Sex Reversals
PLOS Genetics, 2012Co-Authors: Rowena Lavery, Anne-amandine Chassot, Eva Pauper, Elodie P. Gregoire, Muriel Klopfenstein, Norbert B Ghyselinck, Andreas Schedl, Manuel Mark, Dirk G. De Rooij, Marie-christine ChaboissierAbstract:In mammals, male sex determination is governed by SRY-dependent activation of SOX9, whereas female development involves R-spondin1 (RSPO1), an activator of the WNT/beta-catenin signaling pathway. Genetic analyses in mice have demonstrated Sry and SOX9 to be both required and sufficient to induce testicular development. These genes are therefore considered as master regulators of the male pathway. Indeed, female-to-male sex reversal in XX Rspo1 mutant mice correlates with SOX9 expression, suggesting that this transcription factor induces testicular differentiation in pathological conditions. Unexpectedly, here we show that testicular differentiation can occur in XX mutants lacking both Rspo1 and SOX9 (referred to as XX Rspo1KOSOX9cKO), indicating that Sry and SOX9 are dispensable to induce female-to-male sex reversal. Molecular analyses show expression of both Sox8 and Sox10, suggesting that activation of Sox genes other than SOX9 can induce male differentiation in Rspo1KOSOX9cKO mice. Moreover, since testis development occurs in XY Rspo1KOSOX9cKO mice, our data show that Rspo1 is the main effector for male-to-female sex reversal in XY SOX9cKO mice. Thus, Rspo1 is an essential activator of ovarian development not only in normal situations, but also in sex reversal situations. Taken together these data demonstrate that both male and female sex differentiation is induced by distinct, active, genetic pathways. The dogma that considers female differentiation as a default pathway therefore needs to be definitively revised.
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functional analysis of sox8 and SOX9 during sex determination in the mouse
Development, 2004Co-Authors: Marie-christine Chaboissier, Dirk G. De Rooij, Michael Wegner, Richard R. Behringer, Akio Kobayashi, Valerie Vidal, Susanne Lutzkendorf, Henk J G Van De Kant, Andreas SchedlAbstract:Sex determination in mammals directs an initially bipotential gonad to differentiate into either a testis or an ovary. This decision is triggered by the expression of the sex-determining gene Sry, which leads to the activation of male-specific genes including the HMG-box containing gene SOX9. From transgenic studies in mice it is clear that SOX9 is sufficient to induce testis formation. However, there is no direct confirmation for an essential role for SOX9 in testis determination. The studies presented here are the first experimental proof for an essential role for SOX9 in mediating a switch from the ovarian pathway to the testicular pathway. Using conditional gene targeting, we show that homozygous deletion of SOX9 in XY gonads interferes with sex cord development and the activation of the male-specific markers Mis and P450scc, and leads to the expression of the female-specific markers Bmp2 and follistatin. Moreover, using a tissue specific knock-out approach, we show that SOX9 is involved in Sertoli cell differentiation, the activation of Mis and Sox8, and the inactivation of Sry. Finally, double knock-out analyses suggest that Sox8 reinforces SOX9 function in testis differentiation of mice.
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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.
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.
