The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Annick Massacrier - One of the best experts on this subject based on the ideXlab platform.
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Tubacin prevents neuronal migration defects and epileptic activity caused by rat SRPX2 silencing in utero.
Brain - A Journal of Neurology, 2013Co-Authors: Manal Salmi, Annick Massacrier, Nadine Bruneau, Jennifer Cillario, Natalia Lozovaya, Emmanuelle Buhler, Robin Cloarec, Timur Tsintsadze, Françoise Watrin, Vera TsintsadzeAbstract:Altered development of the human cerebral cortex can cause severe malformations with often intractable focal epileptic seizures and may participate in common pathologies, notably epilepsy. This raises important conceptual and therapeutic issues. Two missense mutations in the sushi repeat-containing protein SRPX2 had been previously identified in epileptic disorders with or without structural developmental alteration of the speech cortex. In the present study, we aimed to decipher the precise developmental role of SRPX2, to have a better knowledge on the consequences of its mutations, and to start addressing therapeutic issues through the design of an appropriate animal model. Using an in utero SRPX2 silencing approach, we show that SRPX2 influences neuronal migration in the developing rat cerebral cortex. Wild-type, but not the mutant human SRPX2 proteins, rescued the neuronal migration phenotype caused by SRPX2 silencing in utero, and increased alpha-tubulin acetylation. Following in utero SRPX2 silencing, spontaneous epileptiform activity was recorded post-natally. The neuronal migration defects and the post-natal epileptic consequences were prevented early in embryos by maternal administration of tubulin deacetylase inhibitor tubacin. Hence epileptiform manifestations of developmental origin could be prevented in utero, using a transient and drug-based therapeutic protocol.
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molecular networks implicated in speech related disorders foxp2 regulates the SRPX2 upar complex
Human Molecular Genetics, 2010Co-Authors: Patrice Roll, Annick Massacrier, Sonja C Vernes, Nadine Bruneau, Jennifer Cillario, Magali PonsolelenfantAbstract:It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
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Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex
Human molecular genetics, 2010Co-Authors: Patrice Roll, Gabrielle Rudolf, Annick Massacrier, Sonja C Vernes, Nadine Bruneau, Jennifer Cillario, Magali Ponsole-lenfant, Manal Khalife, Edouard Hirsch, Simon E FisherAbstract:It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
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epileptic and developmental disorders of the speech cortex ligand receptor interaction of wild type and mutant SRPX2 with the plasminogen activator receptor upar
Human Molecular Genetics, 2008Co-Authors: Barbara Royerzemmour, Patrice Roll, Annick Massacrier, Jennifer Cillario, Magali Ponsolelenfant, Hyam Gara, Christian Leveque, Geraldine Ferracci, Andree Robagliaschlupp, Renaud VincentelliAbstract:Mutations in SRPX2 (Sushi-Repeat Protein, X-linked 2) cause rolandic epilepsy with speech impairment (RESDX syndrome) or with altered development of the speech cortex (bilateral perisylvian polymicrogyria). The physiological roles of SRPX2 remain unknown to date. One way to infer the function of SRPX2 relies on the identification of the as yet unknown SRPX2 protein partners. Using a combination of interactome approaches including yeast two-hybrid screening, co-immunoprecipitation experiments, cell surface binding and surface plasmon resonance (SPR), we show that SRPX2 is a ligand for uPAR, the urokinase-type plasminogen activator (uPA) receptor. Previous studies have shown that uPAR -/- knock-out mice exhibited enhanced susceptibility to epileptic seizures and had brain cortical anomalies consistent with altered neuronal migration and maturation, all features that are reminiscent to the phenotypes caused by SRPX2 mutations. SPR analysis indicated that the p.Y72S mutation associated with rolandic epilepsy and perisylvian polymicrogyria, led to a 5.8-fold gain-of-affinity of SRPX2 with uPAR. uPAR is a crucial component of the extracellular plasminogen proteolysis system; two more SRPX2 partners identified here, the cysteine protease cathepsin B (CTSB) and the metalloproteinase ADAMTS4, are also components of the extracellular proteolysis machinery and CTSB is a well-known activator of uPA. The identification of functionally related SRPX2 partners provides the first and exciting insights into the possible role of SRPX2 in the brain, and suggests that a network of SRPX2-interacting proteins classically involved in the proteolytic remodeling of the extracellular matrix and including uPAR participates in the functioning, in the development and in disorders of the speech cortex.
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Epileptic
2008Co-Authors: Barbara Royer-zemmour, Patrice Roll, Annick Massacrier, Magali Ponsole-lenfant, Hyam Gara, Jennifer CillarioAbstract:and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPA
Patrice Roll - One of the best experts on this subject based on the ideXlab platform.
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molecular networks implicated in speech related disorders foxp2 regulates the SRPX2 upar complex
Human Molecular Genetics, 2010Co-Authors: Patrice Roll, Annick Massacrier, Sonja C Vernes, Nadine Bruneau, Jennifer Cillario, Magali PonsolelenfantAbstract:It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
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Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex
Human molecular genetics, 2010Co-Authors: Patrice Roll, Gabrielle Rudolf, Annick Massacrier, Sonja C Vernes, Nadine Bruneau, Jennifer Cillario, Magali Ponsole-lenfant, Manal Khalife, Edouard Hirsch, Simon E FisherAbstract:It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
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epileptic and developmental disorders of the speech cortex ligand receptor interaction of wild type and mutant SRPX2 with the plasminogen activator receptor upar
Human Molecular Genetics, 2008Co-Authors: Barbara Royerzemmour, Patrice Roll, Annick Massacrier, Jennifer Cillario, Magali Ponsolelenfant, Hyam Gara, Christian Leveque, Geraldine Ferracci, Andree Robagliaschlupp, Renaud VincentelliAbstract:Mutations in SRPX2 (Sushi-Repeat Protein, X-linked 2) cause rolandic epilepsy with speech impairment (RESDX syndrome) or with altered development of the speech cortex (bilateral perisylvian polymicrogyria). The physiological roles of SRPX2 remain unknown to date. One way to infer the function of SRPX2 relies on the identification of the as yet unknown SRPX2 protein partners. Using a combination of interactome approaches including yeast two-hybrid screening, co-immunoprecipitation experiments, cell surface binding and surface plasmon resonance (SPR), we show that SRPX2 is a ligand for uPAR, the urokinase-type plasminogen activator (uPA) receptor. Previous studies have shown that uPAR -/- knock-out mice exhibited enhanced susceptibility to epileptic seizures and had brain cortical anomalies consistent with altered neuronal migration and maturation, all features that are reminiscent to the phenotypes caused by SRPX2 mutations. SPR analysis indicated that the p.Y72S mutation associated with rolandic epilepsy and perisylvian polymicrogyria, led to a 5.8-fold gain-of-affinity of SRPX2 with uPAR. uPAR is a crucial component of the extracellular plasminogen proteolysis system; two more SRPX2 partners identified here, the cysteine protease cathepsin B (CTSB) and the metalloproteinase ADAMTS4, are also components of the extracellular proteolysis machinery and CTSB is a well-known activator of uPA. The identification of functionally related SRPX2 partners provides the first and exciting insights into the possible role of SRPX2 in the brain, and suggests that a network of SRPX2-interacting proteins classically involved in the proteolytic remodeling of the extracellular matrix and including uPAR participates in the functioning, in the development and in disorders of the speech cortex.
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Epileptic
2008Co-Authors: Barbara Royer-zemmour, Patrice Roll, Annick Massacrier, Magali Ponsole-lenfant, Hyam Gara, Jennifer CillarioAbstract:and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPA
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implication du gene SRPX2 dans des pathologies de l aire rolandique
Epilepsies, 2007Co-Authors: Patrice Roll, Barbara Royer, Pierre Cau, Gabrielle Rudolf, Edouard Hirsch, Mark Lathrop, Pierre SzepetowskiAbstract:Nous avons identifie un gene localise sur le chromosome X, SRPX2, qui est implique dans une epilepsie rolandique associee a des troubles de la parole et a un retard mental de degre variable. SRPX2 est une proteine secretee a domaines sushi, qui est exprimee dans les neurones cerebraux humains, en particulier dans l’aire rolandique. La mutation identifiee (p. N327S) entraine un gain de glycosylation de la proteine mutee. SRPX2 est aussi responsable, dans une autre famille, d’epilepsie rolandique avec polymicrogyrie perisylvienne bilaterale. Dans cette seconde famille, la mutation identifiee (p. Y72S) est localisee dans le premier domaine sushi. Dans des cellules en culture, ces deux mutations sont associees a des stigmates d’anomalies de conformation proteique. Ces resultats, publies dans Human Molecular Genetics (Roll et al., 2006), vont permettre, en etudiant la proteine SRPX2 et en identifiant ses partenaires, de mettre en evidence des mecanismes physiopathologiques associes au developpement et au fonctionnement de l’aire rolandique.
Pierre Szepetowski - One of the best experts on this subject based on the ideXlab platform.
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sushi repeat protein x linked 2 a novel mediator of angiogenesis
The FASEB Journal, 2009Co-Authors: Marijana Miljkoviclicina, Pierre Szepetowski, Philippe Hammel, Sarah Garridourbani, Paul F Bradfield, Beat A ImhofAbstract:On appropriate stimuli, quiescent endothelial cells start to proliferate and form de novo blood vessels through angiogenesis. To further define molecular mechanisms accompanying the activation of endothelial cells during angiogenesis, we identified genes that were differentially regulated during this process using microarray analyses. In this work, we established a regulatory role for Sushi repeat protein X-linked 2 (SRPX2) in endothelial cell remodeling during angiogenesis. In particular, silencing of SRPX2 using small interfering RNAs (siRNAs) specifically attenuated endothelial cell migration and delayed angiogenic sprout formation. In vivo, SRPX2 expression was detected in de novo formation of blood vessels in angiogenic tissues by in situ mRNA hybridization and immunostaining. Pulldown experiments identified SRPX2 as a ligand for vascular uPAR, a key molecule involved in invasive migration of angiogenic endothelium. Immunostaining revealed coexpression of the SRPX2 and uPAR on vascular endothelium. These findings suggest that SRPX2 regulates endothelial cell migration and tube formation and provides a new target for modulating angiogenesis.
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from rolandic epilepsy to continuous spike and waves during sleep and landau kleffner syndromes insights into possible genetic factors
Epilepsia, 2009Co-Authors: Gabrielle Rudolf, Maria-paola Valenti, Edouard Hirsch, Pierre SzepetowskiAbstract:Epilepsy is a frequent neurologic disease in childhood, characterized by recurrent seizures and sometimes with major effects on social, behavioral, and cognitive development. Childhood focal epilepsies particularly are age-related diseases mainly occurring during developmental critical periods. A complex interplay between brain development and maturation processes and susceptibility genes may contribute to the development of various childhood epileptic syndromes associated with language and cognitive deficits. Indeed, the Landau-Kleffner syndrome (LKS), the continuous spike-and-waves during sleep syndrome (CSWS), and the benign childhood epilepsy with centrotemporal spikes (BCECTS) or benign rolandic epilepsy, are different entities that are considered as part of a single continuous spectrum of disorders. Genetic predisposition with simple to complex modes of inheritance has long been suspected for this wide group of childhood focal epilepsies. Recent reports on the involvement of the SRPX2 and ELP4 genes with possible roles in cell motility, migration, and adhesion have provided first insights into the complex molecular bases of childhood focal epilepsies.
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from rolandic epilepsy to continuous spike and waves during sleep and landau kleffner syndromes insights into possible genetic factors
Epilepsia, 2009Co-Authors: Gabrielle Rudolf, Maria-paola Valenti, Edouard Hirsch, Pierre SzepetowskiAbstract:Epilepsy is a frequent neurologic disease in child-hood, characterized by recurrent seizures andsometimes with major effects on social, behav-ioral, and cognitive development. Childhood focalepilepsies particularly are age-related diseasesmainly occurring during developmental criticalperiods.Acomplex interplay between brain devel-opmentandmaturation processesand susceptibil-ity genes may contribute to the development ofvarious childhood epileptic syndromes associatedwith language and cognitive deficits. Indeed, theLandau-Kleffner syndrome (LKS), the continuousspike-and-waves during sleep syndrome (CSWS),andthebenignchildhoodepilepsywithcentrotem-poralspikes(BCECTS)orbenignrolandicepilepsy,are different entities that are considered as part ofasinglecontinuousspectrumofdisorders.Geneticpredisposition with simple to complex modes ofinheritance has long been suspected for this widegroup of childhood focal epilepsies. Recent reportson the involvement of the SRPX2 and ELP4 geneswith possible roles in cell motility, migration, andadhesion have provided first insights into the com-plexmolecularbasesofchildhoodfocalepilepsies.KEY WORDS:Genetics,Rolandicepilepsy,CSWS,Landau-Kleffner,Speech,SRPX2,ELP4.Childhood epileptic syndromes have relatively specificage-dependentonsetanddisplaytypicallyelectroencepha-lography (EEG) features such as focal sharp waves in thecentrotemporal area, but the causes remain unknown. It iswell established that genetic predisposition plays a majorrole in the etiology of idiopathic epilepsies, whether gen-eralized or focal. Evidence for this genetic contributionhas come from twin studies showing significantly higherconcordance rates in monozygotic than in dizygotic pairs,with focal or even more with generalized epilepsy(Berkovic et al., 1998), and from familial linkage studiesthat in turn have contributed to the identification ofspecific genes (Robinson & Gardiner, 2000; Guerriniet al., 2003; Berkovic et al., 2006; Taylor et al., 2008).Althoughraremonogenicformsofepilepsiesarenowwellrecognized, there is evidence for complex inheritance dueto multiple susceptibility genes in most idiopathic epilep-sies. The aim of this article is to provide further proof,from a review of the literature and personal data, of aninsight into possible genetic factors underlying someformsofidiopathicfocalepilepsiesofchildhood(IFEs).
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Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas
BMC Genetics, 2007Co-Authors: Barbara Royer, Andrée Robaglia-Schlupp, Pierre Cau, Antoine Blancher, Peter Roll, Ronald E Bontrop, Pierre Pontarotti, Dinesh C Soares, Anthony Levasseur, Paul N Barlow, Pierre SzepetowskiAbstract:BackgroundThe X-linked SRPX2 gene encodes a Sushi Repeat-containing Protein of unknown function and is mutated in two disorders of the Rolandic/Sylvian speech areas. Since it is linked to defects in the functioning and the development of brain areas for speech production, SRPX2 may thus have participated in the adaptive organization of such brain regions. To address this issue, we have examined the recent molecular evolution of the SRPX2 gene.ResultsThe complete coding region was sequenced in 24 human X chromosomes from worldwide populations and in six representative nonhuman primate species. One single, fixed amino acid change (R75K) has been specifically incorporated in human SRPX2 since the human-chimpanzee split. The R75K substitution occurred in the first sushi domain of SRPX2, only three amino acid residues away from a previously reported disease-causing mutation (Y72S). Three-dimensional structural modeling of the first sushi domain revealed that Y72 and K75 are both situated in the hypervariable loop that is usually implicated in protein-protein interactions. The side-chain of residue 75 is exposed, and is located within an unusual and SRPX-specific protruding extension to the hypervariable loop. The analysis of non-synonymous/synonymous substitution rate (Ka/Ks) ratio in primates was performed in order to test for positive selection during recent evolution. Using the branch models, the Ka/Ks ratio for the human branch was significantly different (p = 0.027) from that of the other branches. In contrast, the branch-site tests did not reach significance. Genetic analysis was also performed by sequencing 9,908 kilobases (kb) of intronic SRPX2 sequences. Despite low nucleotide diversity, neither the HKA (Hudson-Kreitman-Aguadé) test nor the Tajima's D test reached significance.ConclusionThe R75K human-specific variation occurred in an important functional loop of the first sushi domain of SRPX2, indicating that this evolutionary mutation may have functional importance; however, positive selection for R75K could not be demonstrated. Nevertheless, our data contribute to the first understanding of molecular evolution of the human SPRX2 gene. Further experiments are now required in order to evaluate the possible consequences of R75K on SRPX2 interactions and functioning.
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implication du gene SRPX2 dans des pathologies de l aire rolandique
Epilepsies, 2007Co-Authors: Patrice Roll, Barbara Royer, Pierre Cau, Gabrielle Rudolf, Edouard Hirsch, Mark Lathrop, Pierre SzepetowskiAbstract:Nous avons identifie un gene localise sur le chromosome X, SRPX2, qui est implique dans une epilepsie rolandique associee a des troubles de la parole et a un retard mental de degre variable. SRPX2 est une proteine secretee a domaines sushi, qui est exprimee dans les neurones cerebraux humains, en particulier dans l’aire rolandique. La mutation identifiee (p. N327S) entraine un gain de glycosylation de la proteine mutee. SRPX2 est aussi responsable, dans une autre famille, d’epilepsie rolandique avec polymicrogyrie perisylvienne bilaterale. Dans cette seconde famille, la mutation identifiee (p. Y72S) est localisee dans le premier domaine sushi. Dans des cellules en culture, ces deux mutations sont associees a des stigmates d’anomalies de conformation proteique. Ces resultats, publies dans Human Molecular Genetics (Roll et al., 2006), vont permettre, en etudiant la proteine SRPX2 et en identifiant ses partenaires, de mettre en evidence des mecanismes physiopathologiques associes au developpement et au fonctionnement de l’aire rolandique.
Gabrielle Rudolf - One of the best experts on this subject based on the ideXlab platform.
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A JOURNAL OF NEUROLOGY
2016Co-Authors: Vera Tsintsadze, Gabrielle Rudolf, Claude Villard, Daniel Lafitte, Carlos Cardoso, Lan Bao, Gaetan Lesca, Vanessa Pauly, Ilgam Khalilov, Pascale DurbecAbstract:Tubacin prevents neuronal migration defects and epileptic activity caused by rat SRPX2 silencing in utero Manal Salmi,1,2,3,4, * Nadine Bruneau,1,2,3,4, * Jennifer Cillario,1,2,3,4, * Natalia Lozovaya,1,2,3,5 Annick Massacrier,1,2,3,4 Emmanuelle Buhler,1,2,3,4,6 Robin Cloarec,1,2,3,4 Timur Tsintsadze,1,2,3,
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Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex
Human molecular genetics, 2010Co-Authors: Patrice Roll, Gabrielle Rudolf, Annick Massacrier, Sonja C Vernes, Nadine Bruneau, Jennifer Cillario, Magali Ponsole-lenfant, Manal Khalife, Edouard Hirsch, Simon E FisherAbstract:It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
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from rolandic epilepsy to continuous spike and waves during sleep and landau kleffner syndromes insights into possible genetic factors
Epilepsia, 2009Co-Authors: Gabrielle Rudolf, Maria-paola Valenti, Edouard Hirsch, Pierre SzepetowskiAbstract:Epilepsy is a frequent neurologic disease in childhood, characterized by recurrent seizures and sometimes with major effects on social, behavioral, and cognitive development. Childhood focal epilepsies particularly are age-related diseases mainly occurring during developmental critical periods. A complex interplay between brain development and maturation processes and susceptibility genes may contribute to the development of various childhood epileptic syndromes associated with language and cognitive deficits. Indeed, the Landau-Kleffner syndrome (LKS), the continuous spike-and-waves during sleep syndrome (CSWS), and the benign childhood epilepsy with centrotemporal spikes (BCECTS) or benign rolandic epilepsy, are different entities that are considered as part of a single continuous spectrum of disorders. Genetic predisposition with simple to complex modes of inheritance has long been suspected for this wide group of childhood focal epilepsies. Recent reports on the involvement of the SRPX2 and ELP4 genes with possible roles in cell motility, migration, and adhesion have provided first insights into the complex molecular bases of childhood focal epilepsies.
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from rolandic epilepsy to continuous spike and waves during sleep and landau kleffner syndromes insights into possible genetic factors
Epilepsia, 2009Co-Authors: Gabrielle Rudolf, Maria-paola Valenti, Edouard Hirsch, Pierre SzepetowskiAbstract:Epilepsy is a frequent neurologic disease in child-hood, characterized by recurrent seizures andsometimes with major effects on social, behav-ioral, and cognitive development. Childhood focalepilepsies particularly are age-related diseasesmainly occurring during developmental criticalperiods.Acomplex interplay between brain devel-opmentandmaturation processesand susceptibil-ity genes may contribute to the development ofvarious childhood epileptic syndromes associatedwith language and cognitive deficits. Indeed, theLandau-Kleffner syndrome (LKS), the continuousspike-and-waves during sleep syndrome (CSWS),andthebenignchildhoodepilepsywithcentrotem-poralspikes(BCECTS)orbenignrolandicepilepsy,are different entities that are considered as part ofasinglecontinuousspectrumofdisorders.Geneticpredisposition with simple to complex modes ofinheritance has long been suspected for this widegroup of childhood focal epilepsies. Recent reportson the involvement of the SRPX2 and ELP4 geneswith possible roles in cell motility, migration, andadhesion have provided first insights into the com-plexmolecularbasesofchildhoodfocalepilepsies.KEY WORDS:Genetics,Rolandicepilepsy,CSWS,Landau-Kleffner,Speech,SRPX2,ELP4.Childhood epileptic syndromes have relatively specificage-dependentonsetanddisplaytypicallyelectroencepha-lography (EEG) features such as focal sharp waves in thecentrotemporal area, but the causes remain unknown. It iswell established that genetic predisposition plays a majorrole in the etiology of idiopathic epilepsies, whether gen-eralized or focal. Evidence for this genetic contributionhas come from twin studies showing significantly higherconcordance rates in monozygotic than in dizygotic pairs,with focal or even more with generalized epilepsy(Berkovic et al., 1998), and from familial linkage studiesthat in turn have contributed to the identification ofspecific genes (Robinson & Gardiner, 2000; Guerriniet al., 2003; Berkovic et al., 2006; Taylor et al., 2008).Althoughraremonogenicformsofepilepsiesarenowwellrecognized, there is evidence for complex inheritance dueto multiple susceptibility genes in most idiopathic epilep-sies. The aim of this article is to provide further proof,from a review of the literature and personal data, of aninsight into possible genetic factors underlying someformsofidiopathicfocalepilepsiesofchildhood(IFEs).
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implication du gene SRPX2 dans des pathologies de l aire rolandique
Epilepsies, 2007Co-Authors: Patrice Roll, Barbara Royer, Pierre Cau, Gabrielle Rudolf, Edouard Hirsch, Mark Lathrop, Pierre SzepetowskiAbstract:Nous avons identifie un gene localise sur le chromosome X, SRPX2, qui est implique dans une epilepsie rolandique associee a des troubles de la parole et a un retard mental de degre variable. SRPX2 est une proteine secretee a domaines sushi, qui est exprimee dans les neurones cerebraux humains, en particulier dans l’aire rolandique. La mutation identifiee (p. N327S) entraine un gain de glycosylation de la proteine mutee. SRPX2 est aussi responsable, dans une autre famille, d’epilepsie rolandique avec polymicrogyrie perisylvienne bilaterale. Dans cette seconde famille, la mutation identifiee (p. Y72S) est localisee dans le premier domaine sushi. Dans des cellules en culture, ces deux mutations sont associees a des stigmates d’anomalies de conformation proteique. Ces resultats, publies dans Human Molecular Genetics (Roll et al., 2006), vont permettre, en etudiant la proteine SRPX2 et en identifiant ses partenaires, de mettre en evidence des mecanismes physiopathologiques associes au developpement et au fonctionnement de l’aire rolandique.
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Tubacin prevents neuronal migration defects and epileptic activity caused by rat SRPX2 silencing in utero.
Brain - A Journal of Neurology, 2013Co-Authors: Manal Salmi, Annick Massacrier, Nadine Bruneau, Jennifer Cillario, Natalia Lozovaya, Emmanuelle Buhler, Robin Cloarec, Timur Tsintsadze, Françoise Watrin, Vera TsintsadzeAbstract:Altered development of the human cerebral cortex can cause severe malformations with often intractable focal epileptic seizures and may participate in common pathologies, notably epilepsy. This raises important conceptual and therapeutic issues. Two missense mutations in the sushi repeat-containing protein SRPX2 had been previously identified in epileptic disorders with or without structural developmental alteration of the speech cortex. In the present study, we aimed to decipher the precise developmental role of SRPX2, to have a better knowledge on the consequences of its mutations, and to start addressing therapeutic issues through the design of an appropriate animal model. Using an in utero SRPX2 silencing approach, we show that SRPX2 influences neuronal migration in the developing rat cerebral cortex. Wild-type, but not the mutant human SRPX2 proteins, rescued the neuronal migration phenotype caused by SRPX2 silencing in utero, and increased alpha-tubulin acetylation. Following in utero SRPX2 silencing, spontaneous epileptiform activity was recorded post-natally. The neuronal migration defects and the post-natal epileptic consequences were prevented early in embryos by maternal administration of tubulin deacetylase inhibitor tubacin. Hence epileptiform manifestations of developmental origin could be prevented in utero, using a transient and drug-based therapeutic protocol.
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molecular networks implicated in speech related disorders foxp2 regulates the SRPX2 upar complex
Human Molecular Genetics, 2010Co-Authors: Patrice Roll, Annick Massacrier, Sonja C Vernes, Nadine Bruneau, Jennifer Cillario, Magali PonsolelenfantAbstract:It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
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Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex
Human molecular genetics, 2010Co-Authors: Patrice Roll, Gabrielle Rudolf, Annick Massacrier, Sonja C Vernes, Nadine Bruneau, Jennifer Cillario, Magali Ponsole-lenfant, Manal Khalife, Edouard Hirsch, Simon E FisherAbstract:It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
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epileptic and developmental disorders of the speech cortex ligand receptor interaction of wild type and mutant SRPX2 with the plasminogen activator receptor upar
Human Molecular Genetics, 2008Co-Authors: Barbara Royerzemmour, Patrice Roll, Annick Massacrier, Jennifer Cillario, Magali Ponsolelenfant, Hyam Gara, Christian Leveque, Geraldine Ferracci, Andree Robagliaschlupp, Renaud VincentelliAbstract:Mutations in SRPX2 (Sushi-Repeat Protein, X-linked 2) cause rolandic epilepsy with speech impairment (RESDX syndrome) or with altered development of the speech cortex (bilateral perisylvian polymicrogyria). The physiological roles of SRPX2 remain unknown to date. One way to infer the function of SRPX2 relies on the identification of the as yet unknown SRPX2 protein partners. Using a combination of interactome approaches including yeast two-hybrid screening, co-immunoprecipitation experiments, cell surface binding and surface plasmon resonance (SPR), we show that SRPX2 is a ligand for uPAR, the urokinase-type plasminogen activator (uPA) receptor. Previous studies have shown that uPAR -/- knock-out mice exhibited enhanced susceptibility to epileptic seizures and had brain cortical anomalies consistent with altered neuronal migration and maturation, all features that are reminiscent to the phenotypes caused by SRPX2 mutations. SPR analysis indicated that the p.Y72S mutation associated with rolandic epilepsy and perisylvian polymicrogyria, led to a 5.8-fold gain-of-affinity of SRPX2 with uPAR. uPAR is a crucial component of the extracellular plasminogen proteolysis system; two more SRPX2 partners identified here, the cysteine protease cathepsin B (CTSB) and the metalloproteinase ADAMTS4, are also components of the extracellular proteolysis machinery and CTSB is a well-known activator of uPA. The identification of functionally related SRPX2 partners provides the first and exciting insights into the possible role of SRPX2 in the brain, and suggests that a network of SRPX2-interacting proteins classically involved in the proteolytic remodeling of the extracellular matrix and including uPAR participates in the functioning, in the development and in disorders of the speech cortex.
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Epileptic
2008Co-Authors: Barbara Royer-zemmour, Patrice Roll, Annick Massacrier, Magali Ponsole-lenfant, Hyam Gara, Jennifer CillarioAbstract:and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPA