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Haipeng Guo - One of the best experts on this subject based on the ideXlab platform.
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exacerbated pulmonary arterial hypertension and right ventricular hypertrophy in animals with loss of function of extracellular superoxide dismutase
Hypertension, 2011Co-Authors: Haipeng Guo, John Fassett, Qizhu Tang, Arif Somani, Aron M Geurts, Eric Ostertag, Robert J Bache, Kenneth E Weir, Yingjie ChenAbstract:Studies have demonstrated that increased oxidative stress contributes to the pathogenesis and the development of pulmonary artery hypertension (PAH). Extracellular superoxide dismutase (SOD3) is essential for removing extracellular superoxide anions, and it is highly expressed in lung tissue. However, it is not clear whether endogenous SOD3 can influence the development of PAH. Here we examined the effect of SOD3 knockout on hypoxia-induced PAH in mice and a loss-of-function SOD3 gene mutation (SOD3 E124D ) on monocrotaline (40 mg/kg)-induced PAH in rats. SOD3 knockout significantly exacerbated 2 weeks of hypoxia-induced right ventricular (RV) pressure and RV hypertrophy, whereas RV pressure in SOD3 knockout mice under normoxic conditions is similar to wild-type controls. In untreated control rats at age of 8 weeks, there was no significant difference between wild-type and SOD3 E124D rats in RV pressure and the ratio of RV weight:left ventricular weight (0.25±0.02 in wild-type rats versus 0.25±0.01 in SOD3 E124D rats). However, monocrotaline caused significantly greater increases of RV pressure in SOD3 E124D rats (48.6±1.8 mm Hg in wild-type versus 57.5±3.1 mm Hg in SOD3 E124D rats), of the ratio of RV weight:left ventricular weight (0.41±0.01 versus 0.50±0.09; P E124D rats (55.2±2.3% versus 69.9±2.6%; P
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exacerbated pulmonary arterial hypertension and right ventricular hypertrophy in animals with loss of function of extracellular superoxide dismutase
Hypertension, 2011Co-Authors: Haipeng Guo, John Fassett, Qizhu Tang, Arif Somani, Aron M Geurts, Eric Ostertag, Robert J Bache, Kenneth E Weir, Yingjie ChenAbstract:Studies have demonstrated that increased oxidative stress contributes to the pathogenesis and the development of pulmonary artery hypertension (PAH). Extracellular superoxide dismutase (SOD3) is essential for removing extracellular superoxide anions, and it is highly expressed in lung tissue. However, it is not clear whether endogenous SOD3 can influence the development of PAH. Here we examined the effect of SOD3 knockout on hypoxia-induced PAH in mice and a loss-of-function SOD3 gene mutation (SOD3(E124D)) on monocrotaline (40 mg/kg)-induced PAH in rats. SOD3 knockout significantly exacerbated 2 weeks of hypoxia-induced right ventricular (RV) pressure and RV hypertrophy, whereas RV pressure in SOD3 knockout mice under normoxic conditions is similar to wild-type controls. In untreated control rats at age of 8 weeks, there was no significant difference between wild-type and SOD3(E124D) rats in RV pressure and the ratio of RV weight:left ventricular weight (0.25±0.02 in wild-type rats versus 0.25±0.01 in SOD3(E124D) rats). However, monocrotaline caused significantly greater increases of RV pressure in SOD3(E124D) rats (48.6±1.8 mm Hg in wild-type versus 57.5±3.1 mm Hg in SOD3(E124D) rats), of the ratio of RV weight:left ventricular weight (0.41±0.01 versus 0.50±0.09; P<0.05), and of the percentage of fully muscularized small arterioles in SOD3(E124D) rats (55.2±2.3% versus 69.9±2.6%; P<0.05). Together, these findings indicate that the endogenous SOD3 has no role in the development of PAH under control conditions but plays an important role in protecting the lung from the development of PAH under stress conditions.
Paul Thomas - One of the best experts on this subject based on the ideXlab platform.
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expansion of the lateral ventricles and ependymal deficits underlie the hydrocephalus evident in mice lacking the transcription factor nfix
Brain Research, 2015Co-Authors: Diana Vidovic, Paul Thomas, James N. Hughes, Lachlan Harris, Tracey J Harvey, Yee Hsieh Evelyn Heng, Aaron G Smith, Jason M Osinski, Richard M Gronostajski, Timothy L BaileyAbstract:Nuclear factor one X (NFIX) has been shown to play a pivotal role during the development of many regions of the brain, including the neocortex, the hippocampus and the cerebellum. Mechanistically, NFIX has been shown to promote neural stem cell differentiation through the activation of astrocyte-specific genes and via the repression of genes central to progenitor cell self-renewal. Interestingly, mice lacking Nfix also exhibit other phenotypes with respect to development of the central nervous system, and whose underlying causes have yet to be determined. Here we examine one of the phenotypes displayed by Nfix(-/-) mice, namely hydrocephalus. Through the examination of embryonic and postnatal Nfix(-/-) mice we reveal that hydrocephalus is first seen at around postnatal day (P) 10 in mice lacking Nfix, and is fully penetrant by P20. Furthermore, we examined the subcommissural organ (SCO), the Sylvian aqueduct and the ependymal layer of the lateral ventricles, regions that when malformed and functionally perturbed have previously been implicated in the development of hydrocephalus. SOX3 is a factor known to regulate SCO development. Although we revealed that NFIX could repress SOX3-promoter-driven transcriptional activity in vitro, SOX3 expression within the SCO was normal within Nfix(-/-) mice, and Nfix mutant mice showed no abnormalities in the structure or function of the SCO. Moreover, these mutant mice exhibited no overt blockage of the Sylvian aqueduct. However, the ependymal layer of the lateral ventricles was frequently absent in Nfix(-/-) mice, suggesting that this phenotype may underlie the development of hydrocephalus within these knockout mice.
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Interchromosomal Insertional Translocation at Xq26.3 Alters SOX3 Expression in an Individual With XX Male Sex Reversal
The Journal of Clinical Endocrinology & Metabolism, 2015Co-Authors: Bryan P. Haines, James N. Hughes, Mark A. Corbett, Marie Shaw, Josie Innes, Leena Patel, Jozef Gecz, Jill Clayton-smith, Paul ThomasAbstract:Context: 46,XX male sex reversal occurs in approximately 1: 20 000 live births and is most commonly caused by interchromosomal translocations of the Y-linked sex-determining gene, SRY. Rearrangements of the closely related SOX3 gene on the X chromosome are also associated with 46,XX male sex reversal. It has been hypothesized that sex reversal in the latter is caused by ectopic expression of SOX3 in the developing urogenital ridge where it triggers male development by acting as an analog of SRY. However, altered regulation of SOX3 in individuals with XX male sex reversal has not been demonstrated. Patients and Methods: Here we report a boy with SRY-negative XX male sex reversal who was diagnosed at birth with a small phallus, mixed gonads, and borderline-normal T. Molecular characterization of the affected individual was performed using array comparative genomic hybridization, fluorescent in situ hybridization of metaphase chromosomes, whole-genome sequencing, and RT-PCR expression analysis of lymphoblast...
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XX male sex reversal with genital abnormalities associated with a de novo SOX3 gene duplication.
American Journal of Medical Genetics Part A, 2012Co-Authors: Sharon Moalem, Paul Thomas, Riyana Babul-hirji, Dmitri J Stavropolous, Diane Wherrett, Darius J Bägli, David ChitayatAbstract:Differentiation of the bipotential gonad into testis is initiated by the Y chromosome-linked gene SRY (Sex-determining Region Y) through upregulation of its autosomal direct target gene SOX9 (Sry-related HMG box-containing gene 9). Sequence and chromosome homology studies have shown that SRY most probably evolved from SOX3, which in humans is located at Xq27.1. Mutations causing SOX3 loss-of-function do not affect the sex determination in mice or humans. However, transgenic mouse studies have shown that ectopic expression of SOX3 in the bipotential gonad results in upregulation of Sox9, resulting in testicular induction and XX male sex reversal. However, the mechanism by which these rearrangements cause sex reversal and the frequency with which they are associated with disorders of sex development remains unclear. Rearrangements of the SOX3 locus were identified recently in three cases of human XX male sex reversal. We report on a case of XX male sex reversal associated with a novel de novo duplication of the SOX3 gene. These data provide additional evidence that SOX3 gain-of-function in the XX bipotential gonad causes XX male sex reversal and further support the hypothesis that SOX3 is the evolutionary antecedent of SRY.
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congenital hydrocephalus and abnormal subcommissural organ development in SOX3 transgenic mice
PLOS ONE, 2012Co-Authors: James N. Hughes, Robin Lovellbadge, Michael B. Morris, Karine Rizzoti, Pike See Cheah, Fernando Felquer, Sandra Piltz, Paul ThomasAbstract:Congenital hydrocephalus (CH) is a life-threatening medical condition in which excessive accumulation of CSF leads to ventricular expansion and increased intracranial pressure. Stenosis (blockage) of the Sylvian aqueduct (Aq; the narrow passageway that connects the third and fourth ventricles) is a common form of CH in humans, although the genetic basis of this condition is unknown. Mouse models of CH indicate that Aq stenosis is associated with abnormal development of the subcommmissural organ (SCO) a small secretory organ located at the dorsal midline of the caudal diencephalon. Glycoproteins secreted by the SCO generate Reissner's fibre (RF), a thread-like structure that descends into the Aq and is thought to maintain its patency. However, despite the importance of SCO function in CSF homeostasis, the genetic program that controls SCO development is poorly understood. Here, we show that the X-linked transcription factor SOX3 is expressed in the murine SCO throughout its development and in the mature organ. Importantly, overexpression of SOX3 in the dorsal diencephalic midline of transgenic mice induces CH via a dose-dependent mechanism. Histological, gene expression and cellular proliferation studies indicate that SOX3 overexpression disrupts the development of the SCO primordium through inhibition of diencephalic roof plate identity without inducing programmed cell death. This study provides further evidence that SCO function is essential for the prevention of hydrocephalus and indicates that overexpression of SOX3 in the dorsal midline alters progenitor cell differentiation in a dose-dependent manner.
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transcription factor SOX3 is involved in x linked mental retardation with growth hormone deficiency
American Journal of Human Genetics, 2002Co-Authors: Frederic Laumonnier, Nathalie Ronce, James Lespinasse, Martine Raynaud, Christine Paringaux, Paul Thomas, Vera M. Kalscheuer, Hans Van Bokhoven, Ben C J Hamel, Jean-pierre FrynsAbstract:Physical mapping of the breakpoints of a pericentric inversion of the X chromosome (46,X,inv[X][p21q27]) in a female patient with mild mental retardation revealed localization of the Xp breakpoint in the IL1RAPL gene at Xp21.3 and the Xq breakpoint near the SOX3 gene (SRY [sex determining region Y]-box 3) (GenBank accession number NM_005634) at Xq26.3. Because carrier females with microdeletion in the IL1RAPL gene do not present any abnormal phenotype, we focused on the Xq breakpoint. However, we were unable to confirm the involvement of SOX3 in the mental retardation in this female patient. To validate SOX3 as an X-linked mental retardation (XLMR) gene, we performed mutation analyses in families with XLMR whose causative gene mapped to Xq26-q27. We show here that the SOX3 gene is involved in a large family in which affected individuals have mental retardation and growth hormone deficiency. The mutation results in an in-frame duplication of 33 bp encoding for 11 alanines in a polyalanine tract of the SOX3 gene. The expression pattern during neural and pituitary development suggests that dysfunction of the SOX3 protein caused by the polyalanine expansion might disturb transcription pathways and the regulation of genes involved in cellular processes and functions required for cognitive and pituitary development.
Yingjie Chen - One of the best experts on this subject based on the ideXlab platform.
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exacerbated pulmonary arterial hypertension and right ventricular hypertrophy in animals with loss of function of extracellular superoxide dismutase
Hypertension, 2011Co-Authors: Haipeng Guo, John Fassett, Qizhu Tang, Arif Somani, Aron M Geurts, Eric Ostertag, Robert J Bache, Kenneth E Weir, Yingjie ChenAbstract:Studies have demonstrated that increased oxidative stress contributes to the pathogenesis and the development of pulmonary artery hypertension (PAH). Extracellular superoxide dismutase (SOD3) is essential for removing extracellular superoxide anions, and it is highly expressed in lung tissue. However, it is not clear whether endogenous SOD3 can influence the development of PAH. Here we examined the effect of SOD3 knockout on hypoxia-induced PAH in mice and a loss-of-function SOD3 gene mutation (SOD3 E124D ) on monocrotaline (40 mg/kg)-induced PAH in rats. SOD3 knockout significantly exacerbated 2 weeks of hypoxia-induced right ventricular (RV) pressure and RV hypertrophy, whereas RV pressure in SOD3 knockout mice under normoxic conditions is similar to wild-type controls. In untreated control rats at age of 8 weeks, there was no significant difference between wild-type and SOD3 E124D rats in RV pressure and the ratio of RV weight:left ventricular weight (0.25±0.02 in wild-type rats versus 0.25±0.01 in SOD3 E124D rats). However, monocrotaline caused significantly greater increases of RV pressure in SOD3 E124D rats (48.6±1.8 mm Hg in wild-type versus 57.5±3.1 mm Hg in SOD3 E124D rats), of the ratio of RV weight:left ventricular weight (0.41±0.01 versus 0.50±0.09; P E124D rats (55.2±2.3% versus 69.9±2.6%; P
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exacerbated pulmonary arterial hypertension and right ventricular hypertrophy in animals with loss of function of extracellular superoxide dismutase
Hypertension, 2011Co-Authors: Haipeng Guo, John Fassett, Qizhu Tang, Arif Somani, Aron M Geurts, Eric Ostertag, Robert J Bache, Kenneth E Weir, Yingjie ChenAbstract:Studies have demonstrated that increased oxidative stress contributes to the pathogenesis and the development of pulmonary artery hypertension (PAH). Extracellular superoxide dismutase (SOD3) is essential for removing extracellular superoxide anions, and it is highly expressed in lung tissue. However, it is not clear whether endogenous SOD3 can influence the development of PAH. Here we examined the effect of SOD3 knockout on hypoxia-induced PAH in mice and a loss-of-function SOD3 gene mutation (SOD3(E124D)) on monocrotaline (40 mg/kg)-induced PAH in rats. SOD3 knockout significantly exacerbated 2 weeks of hypoxia-induced right ventricular (RV) pressure and RV hypertrophy, whereas RV pressure in SOD3 knockout mice under normoxic conditions is similar to wild-type controls. In untreated control rats at age of 8 weeks, there was no significant difference between wild-type and SOD3(E124D) rats in RV pressure and the ratio of RV weight:left ventricular weight (0.25±0.02 in wild-type rats versus 0.25±0.01 in SOD3(E124D) rats). However, monocrotaline caused significantly greater increases of RV pressure in SOD3(E124D) rats (48.6±1.8 mm Hg in wild-type versus 57.5±3.1 mm Hg in SOD3(E124D) rats), of the ratio of RV weight:left ventricular weight (0.41±0.01 versus 0.50±0.09; P<0.05), and of the percentage of fully muscularized small arterioles in SOD3(E124D) rats (55.2±2.3% versus 69.9±2.6%; P<0.05). Together, these findings indicate that the endogenous SOD3 has no role in the development of PAH under control conditions but plays an important role in protecting the lung from the development of PAH under stress conditions.
Keun-hong Park - One of the best experts on this subject based on the ideXlab platform.
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Construction of PLGA Nanoparticles Coated with Polycistronic SOX5, SOX6, and SOX9 Genes for Chondrogenesis of Human Mesenchymal Stem Cells.
ACS applied materials & interfaces, 2017Co-Authors: Ji Sun Park, Hye Jin Kim, Seong Min Kim, Jae-hwan Kim, Keun-hong ParkAbstract:Transfection of a cocktail of genes into cells has recently attracted attraction in stem cell differentiation. However, it is not easy to control the transfection rate of each gene. To control and regulate gene delivery into human mesenchymal stem cells (hMSCs), we employed multicistronic genes coupled with a nonviral gene carrier system for stem cell differentiation. Three genes, SOX5, SOX6, and SOX9, were successfully fabricated in a single plasmid. This multicistronic plasmid was complexed with the polycationic polymer polyethylenimine, and poly(lactic-co-glycolic) acid (PLGA) nanoparticles were coated with this complex. The uptake of PLGA nanoparticles complexed with the multicistronic plasmid was tested first. Thereafter, transfection of SOX5, SOX6, and SOX9 was evaluated, which increased the potential for chondrogenesis of hMSCs. The expression of specific genes triggered by transfection of SOX5, SOX6, and SOX9 was tested by RT-PCR and real-time qPCR. Furthermore, specific proteins related to chondr...
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Construction of PLGA Nanoparticles Coated with Polycistronic SOX5, SOX6, and SOX9 Genes for Chondrogenesis of Human Mesenchymal Stem Cells
2016Co-Authors: Ji Sun Park, Hye Jin Kim, Seong Min Kim, Jae-hwan Kim, Keun-hong ParkAbstract:Transfection of a cocktail of genes into cells has recently attracted attraction in stem cell differentiation. However, it is not easy to control the transfection rate of each gene. To control and regulate gene delivery into human mesenchymal stem cells (hMSCs), we employed multicistronic genes coupled with a nonviral gene carrier system for stem cell differentiation. Three genes, SOX5, SOX6, and SOX9, were successfully fabricated in a single plasmid. This multicistronic plasmid was complexed with the polycationic polymer polyethylenimine, and poly(lactic-co-glycolic) acid (PLGA) nanoparticles were coated with this complex. The uptake of PLGA nanoparticles complexed with the multicistronic plasmid was tested first. Thereafter, transfection of SOX5, SOX6, and SOX9 was evaluated, which increased the potential for chondrogenesis of hMSCs. The expression of specific genes triggered by transfection of SOX5, SOX6, and SOX9 was tested by RT-PCR and real-time qPCR. Furthermore, specific proteins related to chondrocytes were investigated by a glycosaminoglycan/DNA assay, Western blotting, histological analyses, and immunofluorescence staining. These methods demonstrated that chondrogenesis of hMSCs treated with PLGA nanoparticles carrying this multicistronic genes was better than that of hMSCs treated with other carriers. Furthermore, the multicistronic genes complexed with PLGA nanoparticles were more simple than that of each single gene complexation with PLGA nanoparticles. Multicistronic genes showed more chondrogenic differentiation than each single gene transfection methods
Benoit De Crombrugghe - One of the best experts on this subject based on the ideXlab platform.
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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: 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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A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene
The EMBO journal, 1998Co-Authors: Benoit De CrombruggheAbstract:Transcripts for a new form of Sox5, called L-Sox5, and Sox6 are coexpressed with Sox9 in all chondrogenic sites of mouse embryos. A coiled-coil domain located in the N-terminal part of L-Sox5, and absent in Sox5, showed >90% identity with a similar domain in Sox6 and mediated homodimerization and heterodimerization with Sox6. Dimerization of L-Sox5/Sox6 greatly increased efficiency of binding of the two Sox proteins to DNA containing adjacent HMG sites. L-Sox5, Sox6 and Sox9 cooperatively activated expression of the chondrocyte differentiation marker Col2a1 in 10T1/2 and MC615 cells. A 48 bp chondrocyte-specific enhancer in this gene, which contains several HMG-like sites that are necessary for enhancer activity, bound the three Sox proteins and was cooperatively activated by the three Sox proteins in non-chondrogenic cells. Our data suggest that L-Sox5/Sox6 and Sox9, which belong to two different classes of Sox transcription factors, cooperate with each other in expression of Col2a1 and possibly other genes of the chondrocytic program.
