12 results on '"Allache R"'
Search Results
2. Identity and nature of neural stem cells in the adult human subventricular zone.
- Author
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Baig S, Nadaf J, Allache R, Le PU, Luo M, Djedid A, Nkili-Meyong A, Safisamghabadi M, Prat A, Antel J, Guiot MC, and Petrecca K
- Abstract
The existence of neural stem cells (NSCs) in adult human brain neurogenic regions remains unresolved. To address this, we created a cell atlas of the adult human subventricular zone (SVZ) derived from fresh neurosurgical samples using single-cell transcriptomics. We discovered 2 adult radial glia (RG)-like populations, aRG1 and aRG2. aRG1 shared features with fetal early RG (eRG) and aRG2 were transcriptomically similar to fetal outer RG (oRG). We also captured early neuronal and oligodendrocytic NSC states. We found that the biological programs driven by their transcriptomes support their roles as early lineage NSCs. Finally, we show that these NSCs have the potential to transition between states and along lineage trajectories. These data reveal that multipotent NSCs reside in the adult human SVZ., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)
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- 2024
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3. Glioblastoma scRNA-seq shows treatment-induced, immune-dependent increase in mesenchymal cancer cells and structural variants in distal neural stem cells.
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Couturier CP, Nadaf J, Li Z, Baig S, Riva G, Le P, Kloosterman DJ, Monlong J, Nkili Meyong A, Allache R, Degenhard T, Al-Rashid M, Guiot MC, Bourque G, Ragoussis J, Akkari L, Quintana FJ, and Petrecca K
- Subjects
- Humans, Lateral Ventricles pathology, Single-Cell Analysis, Tumor Microenvironment, Brain Neoplasms pathology, Glioblastoma pathology, Neural Stem Cells pathology
- Abstract
Background: Glioblastoma is a treatment-resistant brain cancer. Its hierarchical cellular nature and its tumor microenvironment (TME) before, during, and after treatments remain unresolved., Methods: Here, we used single-cell RNA sequencing to analyze new and recurrent glioblastoma and the nearby subventricular zone (SVZ)., Results: We found 4 glioblastoma neural lineages are present in new and recurrent glioblastoma with an enrichment of the cancer mesenchymal lineage, immune cells, and reactive astrocytes in early recurrences. Cancer lineages were hierarchically organized around cycling oligodendrocytic and astrocytic progenitors that are transcriptomically similar but distinct to SVZ neural stem cells (NSCs). Furthermore, NSCs from the SVZ of patients with glioblastoma harbored glioblastoma chromosomal anomalies. Lastly, mesenchymal cancer cells and TME reactive astrocytes shared similar gene signatures which were induced by radiotherapy in a myeloid-dependent fashion in vivo., Conclusion: These data reveal the dynamic, immune-dependent nature of glioblastoma's response to treatments and identify distant NSCs as likely cells of origin., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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4. Author Correction: Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy.
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Couturier CP, Ayyadhury S, Le PU, Nadaf J, Monlong J, Riva G, Allache R, Baig S, Yan X, Bourgey M, Lee C, Wang YCD, Yong VW, Guiot MC, Najafabadi H, Misic B, Antel J, Bourque G, Ragoussis J, and Petrecca K
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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5. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy.
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Couturier CP, Ayyadhury S, Le PU, Nadaf J, Monlong J, Riva G, Allache R, Baig S, Yan X, Bourgey M, Lee C, Wang YCD, Wee Yong V, Guiot MC, Najafabadi H, Misic B, Antel J, Bourque G, Ragoussis J, and Petrecca K
- Subjects
- Adult, Animals, Antineoplastic Agents, Alkylating pharmacology, Brain embryology, Brain Neoplasms pathology, Brain Neoplasms therapy, Cell Survival drug effects, Cell Survival genetics, Cells, Cultured, Female, Fetus, Glioblastoma pathology, Glioblastoma therapy, Humans, Mice, Inbred NOD, Mice, SCID, Neoplastic Stem Cells drug effects, Single-Cell Analysis methods, Temozolomide pharmacology, Xenograft Model Antitumor Assays methods, Brain metabolism, Brain Neoplasms genetics, Glioblastoma genetics, Neoplastic Stem Cells metabolism, Sequence Analysis, RNA methods, Transcriptome genetics
- Abstract
Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.
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- 2020
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6. Identification and characterization of a novel chemically induced allele at the planar cell polarity gene Vangl2.
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El-Hassan AR, Leung V, Kharfallah F, Guyot MC, Allache R, Gros P, and Kibar Z
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- Amino Acid Sequence, Animals, Base Sequence, Crosses, Genetic, Dogs, Female, Genotype, Green Fluorescent Proteins metabolism, Madin Darby Canine Kidney Cells, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Mutant Proteins metabolism, Mutation genetics, Nerve Tissue Proteins chemistry, Nerve Tissue Proteins metabolism, Neural Tube embryology, Neural Tube metabolism, Phenotype, Protein Binding, Protein Stability, Retina metabolism, Subcellular Fractions metabolism, Alleles, Cell Polarity genetics, Nerve Tissue Proteins genetics
- Abstract
Planar cell polarity (PCP) signaling controls a number of morphogenetic processes including convergent extension during gastrulation and neural tube formation. Defects in this pathway cause neural tube defects (NTD), the most common malformations of the central nervous system. The Looptail (Lp) mutant mouse was the first mammalian mutant implicating a PCP gene (Vangl2) in the pathogenesis of NTD. We report on a novel chemically induced mutant allele at Vangl2 called Curly Bob that causes a missense mutation p.Ile268Asn (I268N) in the Vangl2 protein. This mutant segregates in a semi-dominant fashion with heterozygote mice displaying a looped tail appearance, bobbing head, and a circling behavior. Homozygote mutant embryos suffer from a severe form of NTD called craniorachischisis, severe PCP defects in the inner hair cells of the cochlea and posterior cristae, and display a distinct defect in retinal axon guidance. This mutant genetically interacts with the Lp allele (Vangl2
S464N ) in neural tube development and inner ear hair cell polarity. The Vangl2I268N protein variant is expressed at very low levels in affected neural and retinal tissues of mutant homozygote embryos. Biochemical studies show that Vangl2I268N exhibits impaired targeting to the plasma membrane and accumulates in the endoplasmic reticulum. The Vangl2I268N variant no longer physically interacts with its PCP partner DVL3 and has a reduced protein half-life. This mutant provides an important model for dissecting the role of Vangl2 in the development of the neural tube, establishment of polarity of sensory cells of the auditory and vestibular systems, and retinal axon guidance.- Published
- 2018
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7. Scribble1 plays an important role in the pathogenesis of neural tube defects through its mediating effect of Par-3 and Vangl1/2 localization.
- Author
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Kharfallah F, Guyot MC, El Hassan AR, Allache R, Merello E, De Marco P, Di Cristo G, Capra V, and Kibar Z
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- Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins genetics, Carrier Proteins metabolism, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Cell Cycle Proteins, Cell Line, Cell Polarity genetics, Child, Preschool, Female, Heterozygote, Humans, Infant, Male, Membrane Proteins metabolism, Mice, Mice, Knockout, Mutation, Mutation, Missense, Neural Tube Defects genetics, Neural Tube Defects metabolism, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism
- Abstract
Scribble1 (Scrib1) is a tumor suppressor gene that has long been established as an essential component of apicobasal polarity (ABP). In mouse models, mutations in Scrib1 cause a severe form of neural tube defects (NTDs) as a result of a defective planar cell polarity (PCP) signaling. In this study, we dissected the role of Scrib1 in the pathogenesis of NTDs in its mouse mutant Circletail (Crc), in cell lines and in a human NTD cohort. While there were no obvious defects in ABP in the Scrib1Crc/Crc neuroepihelial cells, we identified an abnormal localization of the apical protein Par-3 and of the PCP protein Vangl2. These results were concordant with those obtained following a partial knockdown of Scrib1 in MDCK II cells. Par-3 was able to rescue the localization defect of Vangl1 (paralog of Vangl2) caused by partial knockdown of Scrib1 suggesting that Scrib1 exerts its effect on Vangl1 localization indirectly through Par-3. This conclusion is supported by our findings of an apical enrichment of Vangl1 following a partial knockdown of Par-3. Re-sequencing analysis of SCRIB1 in 473 NTD patients led to the identification of 5 rare heterozygous missense mutations that were predicted to be pathogenic. Two of these mutations, p.Gly263Ser and p.Gln808His, and 2 mouse NTD mutations, p.Ile285Lys and p.Glu814Gly, affected Scrib1 membrane localization and its modulating role of Par-3 and Vangl1 localization. Our study demonstrates an important role of Scrib1 in the pathogenesis of NTDs through its mediating effect of Par-3 and Vangl1/2 localization and most likely independently of ABP., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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8. Genetic studies of ANKRD6 as a molecular switch between Wnt signaling pathways in human neural tube defects.
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Allache R, Wang M, De Marco P, Merello E, Capra V, and Kibar Z
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- Case-Control Studies, Child, Preschool, Cytoskeletal Proteins metabolism, Female, Gene Expression Regulation, Developmental, HEK293 Cells, Humans, Male, Neural Tube Defects metabolism, Protein Interaction Maps, Signal Transduction, Two-Hybrid System Techniques, Cell Polarity, Cytoskeletal Proteins genetics, Mutation, Missense genetics, Neural Tube Defects genetics, Neural Tube Defects pathology, Wnt Signaling Pathway
- Abstract
Background: Planar cell polarity (PCP) is a major branch of Wnt signaling that controls the process of convergent extension in gastrulation and neurulation. PCP defects were associated with neural tube defects (NTDs) that are the most common central nervous system anomalies. PCP signaling is highly dosage sensitive and exhibits an antagonistic relationship with the canonical Wnt/β-catenin pathway. Diversin, encoded by Ankrd6, is an ankyrin repeat protein that activates the non canonical PCP signaling and simultaneously inhibits the canonical pathway., Methods: In this study, we analyzed this dual role of ANKRD6 in NTDs. We sequenced its coding region in 473 NTD patients and 150 controls, and we validated the effect of the identified variants on Wnt signaling using reporter assays in mammalian cells., Results: We identified four rare missense mutations in 0.8% of the NTD patients and two rare missense mutations in 1.3% of the controls. Notably, when all six mutations were validated, only two mutations identified in NTD patients, p.Pro548Leu, p.Arg632His, significantly altered DIVERSIN activity in Wnt signaling assays in a hypomorphic manner., Conclusion: Rare missense mutations in ANKRD6 could affect a balanced reciprocal antagonism between both Wnt pathways in neurulation and act as predisposing factors to NTDs in a subset of patients., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2015
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9. Rare missense variants in DVL1, one of the human counterparts of the Drosophila dishevelled gene, do not confer increased risk for neural tube defects.
- Author
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Merello E, Kibar Z, Allache R, Piatelli G, Cama A, Capra V, and De Marco P
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- Amino Acid Substitution, Animals, Child, Preschool, Cohort Studies, DNA Mutational Analysis, Dishevelled Proteins, Drosophila Proteins, Female, Humans, Male, Mice, Risk Factors, Adaptor Proteins, Signal Transducing genetics, Mutation, Missense, Neural Tube Defects genetics, Phosphoproteins genetics
- Abstract
Background: Neural tube defects (NTDs) are severe malformations that arise when the neural tube fails to close during embryogenesis. The planar cell polarity pathway is involved in neural tube closure and has been implicated in the pathogenesis of NTDs both in animal models and human cohorts. Dishevelled (Dvl/Dsh) is a multi-module protein and a key regulator of both the canonical Wnt and the PCP pathway. In mouse, all Dvl1(-/-) ; Dvl2(-/-) double mutants display craniorachischisis, a severe form of open NTDs. Recently, we have reported a possible role for rare variants of DVL2 as risk factors for NTDs., Methods: In view of these data, we hypothesized that DVL1 mutations might increase the risk for NTDs in some cases. Resequencing of the DVL1 gene in a cohort of 473 NTDs patients and 150 ethnically matched controls was performed. Prediction of the downstream effects of the nonsynonymous variants was done using computational methods., Results: We identified six missense variants that were absent in our ethnically matched controls group, and four of them (p.Arg153Cys; p.Glu544Arg; p.Arg568Trp; p.Val644Phe) were predicted to have a functional effect on protein structure by one or more bioinformatic programs. However, there was no difference in the overall rate of deleterious variants between the patients and controls (four in patients and three in controls; p=0.36)., Conclusion: Our findings did not provide evidence for the implication of DVL1 in the pathogenesis of human NTDs., (Copyright © 2013 Wiley Periodicals, Inc.)
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- 2013
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10. Role of the planar cell polarity gene CELSR1 in neural tube defects and caudal agenesis.
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Allache R, De Marco P, Merello E, Capra V, and Kibar Z
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- Amino Acid Sequence, Animals, Cadherins metabolism, Canada, Cohort Studies, Female, Genotype, Humans, Italy, Male, Molecular Sequence Data, Mutation, Mutation, Missense, Neural Tube Defects ethnology, Neural Tube Defects etiology, Neural Tube Defects pathology, Sequence Analysis, DNA, Cadherins genetics, Cell Polarity genetics, Genetic Predisposition to Disease, Neural Tube Defects genetics, Spine abnormalities
- Abstract
Background: Neural tube defects (NTDs), including anencephaly and spina bifida, have a complex etiology. Defects in the planar cell polarity (PCP) signaling pathway have been strongly associated with NTDs in animal models and human cohorts. In this genetic study, we examined the core PCP gene CELSR1 in NTDs and caudal agenesis cases to determine whether mutations at this gene predispose to these defects., Methods: We sequenced the coding region and the exon-intron junctions of CELSR1 in a cohort of 473 patients affected with various forms of open and closed NTDs (412) or caudal agenesis (61). Novel and rare variants (<1%) were genotyped in a cohort of 639 ethnically-matched individuals. The effect of novel missense mutations absent in controls and in public databases on protein function was predicted in silico., Results: We identified in our cohort one nonsense mutation in exon 1 of CELSR1 that truncates the majority of the protein in one patient with NTD and one in-frame 12 bp deletion that removes a putative PKC phosphorylation "SSR" motif in one caudal agenesis patient. We also detected a total of 13 novel missense variants in 12 patients (11 NTDs and 1 caudal agenesis) that were predicted to be pathogenic in silico., Conclusions: We detected novel CELSR1 mutations predicted to be pathogenic in 2.9% of our NTD cohort and 3.3% of our caudal agenesis cohort. Our findings implicate CELSR1 as a risk factor for NTDs or caudal agenesis and provide additional evidence for a pathogenic role of PCP signaling in these malformations., (Copyright © 2012 Wiley Periodicals, Inc.)
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- 2012
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11. Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects.
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Bosoi CM, Capra V, Allache R, Trinh VQ, De Marco P, Merello E, Drapeau P, Bassuk AG, and Kibar Z
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- Animals, Disease Models, Animal, Female, Humans, Italy, Male, Neural Tube Defects ethnology, Neural Tube Defects metabolism, Neural Tube Defects pathology, United States, Zebrafish genetics, Cell Polarity genetics, LIM Domain Proteins genetics, Mutation, Missense genetics, Neural Tube Defects genetics, Tumor Suppressor Proteins genetics
- Abstract
The planar cell polarity (PCP) pathway controls the process of convergent extension (CE) during gastrulation and neural tube closure, and has been implicated in the pathogenesis of neural tube defects (NTDs) in animal models and human cohorts. In this study, we analyzed the role of one core PCP gene PRICKLE1 in these malformations. We screened this gene in 810 unrelated NTD patients and identified seven rare missense heterozygous mutations that were absent in all controls analyzed and predicted to be functionally deleterious using bioinformatics. Functional validation of five PRICKLE1 variants in a zebrafish model demonstrated that one variant, p.Arg682Cys, antagonized the CE phenotype induced by the wild-type zebrafish prickle1a (zpk1a) in a dominant fashion. Our study demonstrates that PRICKLE1 could act as a predisposing factor to human NTDs and further expands our knowledge of the role of PCP genes in the pathogenesis of these malformations., (© 2011 Wiley Periodicals, Inc.)
- Published
- 2011
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12. Ile481 from the guinea pig alpha-subunit plays a major role in the activation of ENaC by cpt-cAMP.
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Renauld S, Allache R, and Chraibi C
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- Amino Acid Sequence, Animals, Cell Membrane Permeability drug effects, Cyclic AMP pharmacology, Extracellular Space drug effects, Extracellular Space metabolism, Guinea Pigs, Molecular Sequence Data, Mutant Proteins metabolism, Oocytes drug effects, Oocytes metabolism, Perfusion, Protein Structure, Tertiary, Sequence Alignment, Structure-Activity Relationship, Xenopus, Cyclic AMP analogs & derivatives, Epithelial Sodium Channels chemistry, Epithelial Sodium Channels metabolism, Ion Channel Gating drug effects, Isoleucine metabolism, Protein Subunits chemistry, Protein Subunits metabolism, Thionucleotides pharmacology
- Abstract
The epithelial sodium channel (ENaC) is the major rate-limiting step for vasopressin and aldosterone sensitive Na(+) reabsorption across kidney epithelia. Recently, ENaC activity was shown to be modulated by extracellular factors such as proteases, Na(+) ion and several other elements. However, the molecular mechanisms of these actions remain unclear. We and others have shown that ENaC composed of the guinea-pig alpha-subunit (alphagp), and the beta gamma rat subunits (betargammar) could be activated by cpt-cAMP, a cAMP analogue, through a mechanism not involving the cAMP-PKA pathway. In the present study, we confirmed by patch-clamp experiments on Xenopus oocytes that the number of open channels increased by 2.4-fold after cpt-cAMP exposure. In order to characterize the extracellular domain involved in this activation, we generated alpha-subunit chimera's harboring different portions of the extracellular loop of the alphagp and alphar. Using two-electrode voltage-clamp, we established that Tyr456-Ser532 from the alphagp confers sensibility to cpt-AMP. Then, by site-directed mutagenesis, we have isolated Ile481 as a major residue for cpt-cAMP-dependant activation. Taken together, these experiments provide evidence of an extracellular-ligand stimulating ENaC. They also contribute to the further understanding of the structure-function relationship of this channel., (Copyright 2008 S. Karger AG, Basel.)
- Published
- 2008
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