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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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SOX6 is necessary for efficient erythropoiesis in adult mice under physiological and anemia-induced stress conditions.
PloS one, 2010Co-Authors: Bogdan Dumitriu, Pallavi Bhattaram, Yuanshuai Huang, Nayeem Quayum, Jan Jensen, Véronique LefebvreAbstract:Background: Definitive erythropoiesis is a vital process throughout life. Both its basal activity under physiological conditions and its increased activity under anemia-induced stress conditions are highly stimulated by the hormone erythropoietin. The transcription factor SOX6 was previously shown to enhance fetal erythropoiesis together and beyond erythropoietin signaling, but its importance in adulthood and mechanisms of action remain unknown. We used here SOX6 conditional null mice and molecular assays to address these questions. Methodology/Principal Findings: SOX6 fl/fl ErGFPCre adult mice, which lacked SOX6 in erythroid cells, exhibited compensated anemia, erythroid cell developmental defects, and anisocytotic, short-lived red cells under physiological conditions, proving that SOX6 promotes basal erythropoiesis. Tamoxifen treatment of SOX6 fl/fl CaggCreER mice induced widespread inactivation of SOX6 in a timely controlled manner and resulted in erythroblast defects before reticulocytosis, demonstrating that impaired erythropoiesis is a primary cause rather than consequence of anemia in the absence of SOX6. Twenty five percent of SOX6 fl/fl ErGFPCre mice died 4 or 5 days after induction of acute anemia with phenylhydrazine. The others recovered slowly. They promptly increased their erythropoietin level and amplified their erythroid progenitor pool, but then exhibited severe erythroblast and reticulocyte defects. SOX6 is thus essential in the maturation phase of stress erythropoiesis that follows the erythropoietin-dependent amplification phase. SOX6 inactivation resulted in upregulation of embryonic globin genes, but embryonic globin chains remained scarce and apparently inconsequential. SOX6 inactivation also resulted in downregulation of erythroid terminal markers, including the Bcl2l1 gene for the anti-apoptotic factor Bcl-xL, and in vitro assays indicated that SOX6 directly upregulates Bcl2l1 downstream of and beyond erythropoietin signaling. Conclusions/Significance: This study demonstrates that SOX6 is necessary for efficient erythropoiesis in adult mice under both basal and stress conditions. It is primarily involved in enhancing the survival rate and maturation process of erythroid cells and acts at least in part by upregulating Bcl2l1. Citation: Dumitriu B, Bhattaram P, Dy P, Huang Y, Quayum N, et al. (2010) SOX6 Is Necessary for Efficient Erythropoiesis in Adult Mice under Physiological and
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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.
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.
Chia-feng Liu - 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.
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, C. Claus 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.
Richard R. Behringer - One of the best experts on this subject based on the ideXlab platform.
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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.
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The transcription factors L-Sox5 and SOX6 are essential for cartilage formation
Developmental cell, 2001Co-Authors: Patrick Smits, Benoit De Crombrugghe, Richard R. Behringer, Jennifer Mandel, Zhaoping Zhang, Jian Ming Deng, Véronique LefebvreAbstract:Cartilages form the primary skeleton of vertebrate embryos, ensure its rapid growth, and provide mandatory templates upon which definitive bone is progressively laid down. Chondrogenesis is effected by a single cell type, the chondrocyte, which is of mesenchymal origin. Chondrocytes sequentially fulfill the different functions of cartilages by undergoing multiple steps of differentiation. Our main interest over recent years has been to identify transcription factors that specifically control the chondrocyte differentiation pathway. We found that L-Sox5, SOX6, and Sox9 were able to bind and activate a cartilage-specific enhancer of collagen type 2 gene (Col2a1) and were specifically co-expressed with Col2a1 during chondrogenesis in vivo. These data, supported by the notion that many Sox factors control cell fate determination in various lineages, strongly suggested that L-Sox5, SOX6, and Sox9 act as master chondrogenic transcription factors. This hypothesis was tested and confirmed by assessing the consequences of the null mutation of their genes on mouse embryo development. We review here these studies, with a special emphasis on LSoxS and SOX6. Akiyama and collaborators address the role of Sox9 in an accompanying review.