The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
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 Menzelsevering, Michael Wegner, Matthias Zenkel, Naresh Polisetti, Friedrich E. Kruse, Elisabeth Sock, Ursula SchlotzerschrehardtAbstract: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-3s), a negative regulator of Wnt/s-catenin signaling. Sox9 expression, in turn, was significantly suppressed by treatment of LEPCs with exogenous GSK-3s inhibitors and enhanced by small molecule inhibitors of Wnt signaling. Our results suggest that Sox9 and Wnt/s-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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evolutionary conserved sequence elements with embryonic enhancer activity in the vicinity of the mammalian SOX8 gene
The International Journal of Biochemistry & Cell Biology, 2010Co-Authors: Sabine Guth, Michael R Bosl, Elisabeth Sock, Michael WegnerAbstract:The transcription factor SOX8 is widely and dynamically expressed during embryonic development similar to its close relatives Sox9 and Sox10. Whereas gene-regulatory sequences have been identified in the vicinity of the Sox9 and Sox10 genes, no such sequences are known for SOX8. Here we used sequence conservation between mammals and birds to identify seven regions near the SOX8 gene as potential enhancers. Of these sequences, three indeed functioned as SOX8-specific enhancers in transgenic embryos. They were all localized in the upstream region of the SOX8 gene and distal to the promoter which by itself failed to drive significant transgene expression during embryogenesis. Tissues in which at least one of the three enhancers was active and that are known to express SOX8, included facial mesenchyme, the first branchial arch, peripheral nervous system and other neural crest derivatives as well as central nervous system, eye and limb. Other prominent sites of embryonic SOX8 expression were, however, not covered by the three enhancers arguing that additional enhancers exist that may be not conserved in their sequence between mammals and birds or located outside the 220 kb genomic interval analyzed in this study.
Veronique Lefebvre - One of the best experts on this subject based on the ideXlab platform.
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the soxe transcription factors SOX8 sox9 and sox10 share a bi partite transactivation mechanism
Nucleic Acids Research, 2019Co-Authors: Abdul Haseeb, Veronique LefebvreAbstract:SOX8, SOX9 and SOX10 compose the SOXE transcription factor group. They govern cell fate and differentiation in many lineages, and mutations impairing their activity cause severe diseases, including campomelic dysplasia (SOX9), sex determination disorders (SOX8 and SOX9) and Waardenburg-Shah syndrome (SOX10). However, incomplete knowledge of their modes of action limits disease understanding. We here uncover that the proteins share a bipartite transactivation mechanism, whereby a transactivation domain in the middle of the proteins (TAM) synergizes with a C-terminal one (TAC). TAM comprises amphipathic α-helices predicted to form a protein-binding pocket and overlapping with minimal transactivation motifs (9-aa-TAD) described in many transcription factors. One 9-aa-TAD sequence includes an evolutionarily conserved and functionally required EΦ[D/E]QYΦ motif. SOXF proteins (SOX7, SOX17 and SOX18) contain an identical motif, suggesting evolution from a common ancestor already harboring this motif, whereas TAC and other transactivating SOX proteins feature only remotely related motifs. Missense variants in this SOXE/SOXF-specific motif are rare in control individuals, but have been detected in cancers, supporting its importance in development and physiology. By deepening understanding of mechanisms underlying the central transactivation function of SOXE proteins, these findings should help further decipher molecular networks essential for development and health and dysregulated in diseases.
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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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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.
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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: Veronique 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.
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l sox5 and sox6 drive expression of the aggrecan gene in cartilage by securing binding of sox9 to a far upstream enhancer
Molecular and Cellular Biology, 2008Co-Authors: Yu Han, Veronique LefebvreAbstract:The Sry-related high-mobility-group box transcription factor Sox9 recruits the redundant L-Sox5 and Sox6 proteins to effect chondrogenesis, but the mode of action of the trio remains unclear. We identify here a highly conserved 359-bp sequence 10 kb upstream of the Agc1 gene for aggrecan, a most essential cartilage proteoglycan and key marker of chondrocyte differentiation. This sequence directs expression of a minimal promoter in both embryonic and adult cartilage in transgenic mice, in a manner that matches Agc1 expression. The chondrogenic trio is required and sufficient to mediate the activity of this enhancer. It acts directly, Sox9 binding to a critical cis-acting element and L-Sox5/Sox6 binding to three additional elements, which are cooperatively needed. Upon binding to their specific sites, L-Sox5/Sox6 increases the efficiency of Sox9 binding to its own recognition site and thereby robustly potentiates the ability of Sox9 to activate the enhancer. L-Sox5/Sox6 similarly secures Sox9 binding to Col2a1 (encoding collagen-2) and other cartilage-specific enhancers. This study thus uncovers critical cis-acting elements and transcription factors driving Agc1 expression in cartilage and increases understanding of the mode of action of the chondrogenic Sox trio.
Elisabeth Sock - 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 Menzelsevering, Michael Wegner, Matthias Zenkel, Naresh Polisetti, Friedrich E. Kruse, Elisabeth Sock, Ursula SchlotzerschrehardtAbstract: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-3s), a negative regulator of Wnt/s-catenin signaling. Sox9 expression, in turn, was significantly suppressed by treatment of LEPCs with exogenous GSK-3s inhibitors and enhanced by small molecule inhibitors of Wnt signaling. Our results suggest that Sox9 and Wnt/s-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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evolutionary conserved sequence elements with embryonic enhancer activity in the vicinity of the mammalian SOX8 gene
The International Journal of Biochemistry & Cell Biology, 2010Co-Authors: Sabine Guth, Michael R Bosl, Elisabeth Sock, Michael WegnerAbstract:The transcription factor SOX8 is widely and dynamically expressed during embryonic development similar to its close relatives Sox9 and Sox10. Whereas gene-regulatory sequences have been identified in the vicinity of the Sox9 and Sox10 genes, no such sequences are known for SOX8. Here we used sequence conservation between mammals and birds to identify seven regions near the SOX8 gene as potential enhancers. Of these sequences, three indeed functioned as SOX8-specific enhancers in transgenic embryos. They were all localized in the upstream region of the SOX8 gene and distal to the promoter which by itself failed to drive significant transgene expression during embryogenesis. Tissues in which at least one of the three enhancers was active and that are known to express SOX8, included facial mesenchyme, the first branchial arch, peripheral nervous system and other neural crest derivatives as well as central nervous system, eye and limb. Other prominent sites of embryonic SOX8 expression were, however, not covered by the three enhancers arguing that additional enhancers exist that may be not conserved in their sequence between mammals and birds or located outside the 220 kb genomic interval analyzed in this study.
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impact of transcription factor SOX8 on oligodendrocyte specification in the mouse embryonic spinal cord
Developmental Biology, 2005Co-Authors: Claus C Stolt, Petra Lommes, Elisabeth Sock, Simone Schmitt, Michael WegnerAbstract:The myelin-forming oligodendrocytes of the mouse embryonic spinal cord express the three group E Sox proteins SOX8, Sox9, and Sox10. They require Sox9 for their specification from neuroepithelial cells of the ventricular zone and Sox10 for their terminal differentiation and myelination. Here, we show that during oligodendrocyte development, SOX8 is expressed after Sox9, but before Sox10. Loss of SOX8 did not impair oligodendrocyte specification by itself, but enhanced the Sox9-dependent defect. Oligodendrocyte progenitors were still generated in the Sox9-deficient spinal cord, albeit at 20-fold lower rates than in the wildtype. Combined loss of SOX8 and Sox9, in contrast, led to a near complete loss of oligodendrocytes. Other cell types such as ventricular zone cells and radial glia remained unaffected in their numbers as well as their rates of proliferation and apoptosis. Oligodendrocyte development thus relies on the differential contribution of all three group E Sox proteins at various phases.
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idiopathic weight reduction in mice deficient in the high mobility group transcription factor SOX8
Molecular and Cellular Biology, 2001Co-Authors: Elisabeth Sock, Katy Schmidt, Irm Hermannsborgmeyer, Michael R Bosl, Michael WegnerAbstract:The Sox protein family constitutes a group of transcription factors with an already large but still increasing number of family members. Its occurrence is confined to the animal kingdom, where Sox proteins have diverse functions both during development and in the adult. These functions range from roles in early embryogenesis to functions in lineage specification and terminal differentiation events. Processes known to rely on Sox proteins include endoderm formation, neural induction, neural crest and lens development, gliogenesis, chondrogenesis, hemopoiesis, and sex determination (for reviews, see references 5, 22, and 32). All family members are characterized by possession of a specific type of DNA-binding domain, the minor groove-interacting high-mobility-group domain. Sequence similarities outside this domain are found only between subsets of Sox proteins and provide criteria which further subdivide this protein family into subgroups A to G. These subgroups are present in organisms from Caenorhabditis elegans and Drosophila to humans (5, 32). Genes coding for Sox proteins of the same subgroup tend to have similar genomic organizations. One of the well-characterized groups of Sox proteins is subgroup E. It consists of the three members SOX8, Sox9, and Sox10, with SOX8 being the most recently identified (23, 25). Inactivation of a single Sox9 allele in humans is the cause of a severe skeletal malformation syndrome called campomelic dysplasia (7, 31). In male patients, campomelic dysplasia is often associated with XY sex reversal. In agreement with the observed phenotype, Sox9 expression is highest in chondrocytes and Sertoli cells of the testis (13, 17, 33). Other expression domains of Sox9 include brain, otic and nasal placode, lung, and kidney. These tissues are only rarely affected in campomelic dysplasia patients. The severity of the phenotype already observed in the heterozygous state might also explain why standard gene disruption techniques in mice have proven unsuccessful for Sox9. When homozygous Sox9-deficient ES cells were used to generate chimeras, Sox9-deficient ES cells failed to contribute to the chondrocyte population in these chimeric mice, impressively proving the essential role of Sox9 in this cell type (4). Many chondrocyte-specific genes are furthermore under direct control of Sox9, including the genes for type II collagen, type XI collagen, aggrecan, and cartilage-derived retinoic acid-sensitive protein genes (1, 15, 16, 26, 34). Sox10 on the other hand, is expressed first in the early neural crest, then throughout the forming peripheral nervous system (PNS), and finally in glial cells of the PNS and central nervous system (CNS) (14). As in the case of Sox9, mutation or loss of a single Sox10 allele is already phenotypically apparent. Sox10 haploinsufficiency causes disturbances of neural crest development that are visible as partial pigmentation defects and aganglionosis of the distal colon in mice and humans (6, 9, 24, 28). In humans, this defect is known as Waardenburg-Hirschsprung disease. Peripheral neuropathies are often associated with Sox10-dependent Waardenburg-Hirschsprung disease (27, 29), correlating with the strong expression of Sox10 at later times in peripheral glia (14). Central myelinopathies present a further, less frequent complication (11), in agreement with Sox10 expression in myelinating glia of the CNS (14). Inactivation or deletion of both Sox10 alleles in mice leads to a complete loss of neural crest-derived melanocytes and enteric nervous system and proves that Sox10 is an essential factor for all gliogenesis of the PNS (6, 21). Target genes of Sox10 include genes important for glial development (ErbB3 gene) and identity (protein zero gene) (6, 21). Recently, SOX8 was identified as the third group E Sox protein in mice, humans, and chickens (2, 23, 25). Existing reports on SOX8 expression are preliminary and partially contradictory, but they hint at expression during development in many tissues and organs, including branchial arches, nervous system, eye, male gonad, kidney, and limbs. Prominent places of expression in the adult were brain and testis. Chromosomal localization of human SOX8 to 16p13.3 placed it in a region often deleted in patients with ATR-16 syndrome (characterized by a combination of α-thalassemia, facial malformations, and mental retardation) and targeted in a Japanese family by a translocation event causing microphthalmia and congenital cataract (microphthalmia-cataract syndrome [CATM]). Localization to the syntenic region on mouse chromosome 17 places SOX8 in proximity to the tw18 mutation which causes abnormal mesodermal cell migration and is lethal prior to organogenesis. In analogy to the case for Sox9 and Sox10, it appeared reasonable to assume that inactivation or deletion of SOX8 in mice should cause severe developmental defects in some of the tissues that express it. The phenotype could then be instrumental in identifying SOX8-dependent disease phenotypes in humans. Here, we deleted the SOX8 gene by homologous recombination in ES cells and subsequently generated SOX8-deficient mice. The simultaneous replacement of the SOX8 gene by a lacZ marker allowed a detailed analysis of SOX8 expression and should have facilitated detection of developmental defects in these mice. Surprisingly, homozygous SOX8-deficient mice failed to exhibit a major developmental defect in any of the SOX8-specific expression domains. Despite a significant weight reduction, they were viable and fertile. Possible reasons for and implications of this unexpected finding are discussed.
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idiopathic weight reduction in mice deficient in the high mobility group transcription factor SOX8
Molecular and Cellular Biology, 2001Co-Authors: Elisabeth Sock, Katy Schmidt, Irm Hermannsborgmeyer, Michael R Bosl, Michael WegnerAbstract:SOX8, Sox9, and Sox10 constitute subgroup E within the Sox family of transcription factors. Many Sox proteins are essential regulators of development. Sox9, for instance, is required for chondrogenesis and male sex determination; Sox10 plays key roles in neural crest development and peripheral gliogenesis. The function of SOX8 has not been studied so far. Here, we generated mice deficient in this third member of subgroup E. In analogy to the case for the related Sox9 and Sox10, we expected severe developmental defects in these mice. Despite strong expression of SOX8 in many tissues, including neural crest, nervous system, muscle, cartilage, adrenal gland, kidney, and testis, homozygous mice developed normally in utero, were born at Mendelian frequencies, and were viable. A substantial reduction in weight was observed in these mice; however, this reduction was not attributable to significant structural deficits in any of the SOX8-expressing tissues. Because of frequent coexpression with either Sox9 or Sox10, the mild phenotype of SOX8-deficient mice might at least in part be due to functional redundancy between group E Sox proteins.
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: Veronique 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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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, Veronique 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.
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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functional analysis of SOX8 and sox9 during sex determination in the mouse
Development, 2004Co-Authors: Marie-christine Chaboissier, Dirk G. De Rooij, Michael Wegner, 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.