Génétique de la déficience intellectuelle / Laurence COLLEAUX

Public ISBD in La déficience intellectuelle face aux progrès des neurosciences / Roland BROCA Titre : Génétique de la déficience intellectuelle Type de document : texte imprimé Auteurs : Laurence COLLEAUX, Auteur Année de publication : 2013 Importance : p.49-60 Langues : Français (fre) Index. décimale : TRO-C TRO-C - Déficience Intellectuelle Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=222 in La déficience intellectuelle face aux progrès des neurosciences / Roland BROCA Génétique de la déficience intellectuelle [texte imprimé] / Laurence COLLEAUX, Auteur . - 2013 . - p.49-60. Langues : Français (fre) Index. décimale : TRO-C TRO-C - Déficience Intellectuelle Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=222

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Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits / Julien FREGEAC in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 22 p. Titre : Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits Type de document : texte imprimé Auteurs : Julien FREGEAC, Auteur ; Stéphanie MORICEAU, Auteur ; Antoine POLI, Auteur ; Lam Son NGUYEN, Auteur ; Franck OURY, Auteur ; Laurence COLLEAUX, Auteur Article en page(s) : 22 p. Langues : Anglais (eng) Mots-clés : Hippocampus-dependent cognitive functions  MicroRNA  Neural stem cells differentiation  Neurodevelopment  Neurodevelopmental disorders  miR-146a Index. décimale : PER Périodiques Résumé : BACKGROUND: Formation and maintenance of appropriate neural networks require tight regulation of neural stem cell proliferation, differentiation, and neurogenesis. microRNAs (miRNAs) play an important role in brain development and plasticity, and dysregulated miRNA profiles have been linked to neurodevelopmental disorders including autism, schizophrenia, or intellectual disability. Yet, the functional role of miRNAs in neural development and postnatal brain functions remains unclear. METHODS: Using a combination of cell biology techniques as well as behavioral studies and brain imaging, we characterize mouse models with either constitutive inactivation or selectively hippocampal knockdown of the neurodevelopmental disease-associated gene Mir146a, the most commonly deregulated miRNA in developmental brain disorders (DBD). RESULTS: We first show that during development, loss of miR-146a impairs the differentiation of radial glial cells, neurogenesis process, and neurite extension. In the mouse adult brain, loss of miR-146a correlates with an increased hippocampal asymmetry coupled with defects in spatial learning and memory performances. Moreover, selective hippocampal downregulation of miR-146a in adult mice causes severe hippocampal-dependent memory impairments indicating for the first time a role for this miRNA in postnatal brain functions. CONCLUSION: Our results show that miR-146a expression is critical for correct differentiation of neural stem cell during brain development and provide for the first time a strong argument for a postnatal role of miR-146a in regulating hippocampal-dependent memory. Furthermore, the demonstration that the Mir146a(-/-) mouse recapitulates several aspects reported in DBD patients, including impaired neurogenesis, abnormal brain anatomy, and working and spatial memories deficits, provides convincing evidence that the dysregulation of miR146a contributes to the pathogenesis of DBDs. En ligne : http://dx.doi.org/10.1186/s13229-020-00328-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits [texte imprimé] / Julien FREGEAC, Auteur ; Stéphanie MORICEAU, Auteur ; Antoine POLI, Auteur ; Lam Son NGUYEN, Auteur ; Franck OURY, Auteur ; Laurence COLLEAUX, Auteur . - 22 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 22 p. Mots-clés : Hippocampus-dependent cognitive functions  MicroRNA  Neural stem cells differentiation  Neurodevelopment  Neurodevelopmental disorders  miR-146a Index. décimale : PER Périodiques Résumé : BACKGROUND: Formation and maintenance of appropriate neural networks require tight regulation of neural stem cell proliferation, differentiation, and neurogenesis. microRNAs (miRNAs) play an important role in brain development and plasticity, and dysregulated miRNA profiles have been linked to neurodevelopmental disorders including autism, schizophrenia, or intellectual disability. Yet, the functional role of miRNAs in neural development and postnatal brain functions remains unclear. METHODS: Using a combination of cell biology techniques as well as behavioral studies and brain imaging, we characterize mouse models with either constitutive inactivation or selectively hippocampal knockdown of the neurodevelopmental disease-associated gene Mir146a, the most commonly deregulated miRNA in developmental brain disorders (DBD). RESULTS: We first show that during development, loss of miR-146a impairs the differentiation of radial glial cells, neurogenesis process, and neurite extension. In the mouse adult brain, loss of miR-146a correlates with an increased hippocampal asymmetry coupled with defects in spatial learning and memory performances. Moreover, selective hippocampal downregulation of miR-146a in adult mice causes severe hippocampal-dependent memory impairments indicating for the first time a role for this miRNA in postnatal brain functions. CONCLUSION: Our results show that miR-146a expression is critical for correct differentiation of neural stem cell during brain development and provide for the first time a strong argument for a postnatal role of miR-146a in regulating hippocampal-dependent memory. Furthermore, the demonstration that the Mir146a(-/-) mouse recapitulates several aspects reported in DBD patients, including impaired neurogenesis, abnormal brain anatomy, and working and spatial memories deficits, provides convincing evidence that the dysregulation of miR146a contributes to the pathogenesis of DBDs. En ligne : http://dx.doi.org/10.1186/s13229-020-00328-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology / Lam Son NGUYEN in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 1p. Titre : Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology Type de document : texte imprimé Auteurs : Lam Son NGUYEN, Auteur ; Marylin LEPLEUX, Auteur ; Mélanie MAKHLOUF, Auteur ; Christelle MARTIN, Auteur ; Julien FREGEAC, Auteur ; Karine SIQUIER-PERNET, Auteur ; Alain PHILIPPE, Auteur ; François FERON, Auteur ; Bruno GEPNER, Auteur ; Claire ROUGEULLE, Auteur ; Yann HUMEAU, Auteur ; Laurence COLLEAUX, Auteur Article en page(s) : 1p. Langues : Anglais (eng) Mots-clés : 3' Untranslated Regions/genetics  Adult  Adult Stem Cells/metabolism  Animals  Astrocytes/metabolism  Autism Spectrum Disorder/genetics/pathology/physiopathology  Cells, Cultured  Female  Fibroblasts/metabolism  Genetic Vectors/genetics  Hippocampus/cytology/embryology  Humans  Lentivirus/genetics  Male  Mice  MicroRNAs/genetics/physiology  Neurons/metabolism/ultrastructure  Olfactory Mucosa/pathology  Organ Specificity  Real-Time Polymerase Chain Reaction  Transcriptome  Young Adult  Astrocyte  Autism spectrum disorders  MicroRNA  Neuron  Olfactory mucosa stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. METHODS: miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. RESULTS: We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients' cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. CONCLUSIONS: While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic. En ligne : http://dx.doi.org/10.1186/s13229-015-0064-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 [article] Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology [texte imprimé] / Lam Son NGUYEN, Auteur ; Marylin LEPLEUX, Auteur ; Mélanie MAKHLOUF, Auteur ; Christelle MARTIN, Auteur ; Julien FREGEAC, Auteur ; Karine SIQUIER-PERNET, Auteur ; Alain PHILIPPE, Auteur ; François FERON, Auteur ; Bruno GEPNER, Auteur ; Claire ROUGEULLE, Auteur ; Yann HUMEAU, Auteur ; Laurence COLLEAUX, Auteur . - 1p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 1p. Mots-clés : 3' Untranslated Regions/genetics  Adult  Adult Stem Cells/metabolism  Animals  Astrocytes/metabolism  Autism Spectrum Disorder/genetics/pathology/physiopathology  Cells, Cultured  Female  Fibroblasts/metabolism  Genetic Vectors/genetics  Hippocampus/cytology/embryology  Humans  Lentivirus/genetics  Male  Mice  MicroRNAs/genetics/physiology  Neurons/metabolism/ultrastructure  Olfactory Mucosa/pathology  Organ Specificity  Real-Time Polymerase Chain Reaction  Transcriptome  Young Adult  Astrocyte  Autism spectrum disorders  MicroRNA  Neuron  Olfactory mucosa stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. METHODS: miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. RESULTS: We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients' cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. CONCLUSIONS: While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic. En ligne : http://dx.doi.org/10.1186/s13229-015-0064-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328

Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders / Lam Son NGUYEN in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 38p. Titre : Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders Type de document : texte imprimé Auteurs : Lam Son NGUYEN, Auteur ; Julien FREGEAC, Auteur ; Christine BOLE-FEYSOT, Auteur ; Nicolas CAGNARD, Auteur ; Anand IYER, Auteur ; Jasper ANINK, Auteur ; Eleonora ARONICA, Auteur ; Olivier ALIBEU, Auteur ; Patrick NITSCHKÉ, Auteur ; Laurence COLLEAUX, Auteur Article en page(s) : 38p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics/metabolism  Cell Line  Cell Lineage  Child  Female  Humans  Male  MicroRNAs/genetics/metabolism  Neural Stem Cells/cytology/metabolism  Neurogenesis  Temporal Lobe/cytology/metabolism  Up-Regulation  Autism spectrum disorders  Human neural stem cell  Transcriptome  microRNA Index. décimale : PER Périodiques Résumé : Background: MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs have emerged as important modulators of brain development and neuronal function and are implicated in several neurological diseases. Previous studies found miR-146a upregulation is the most common miRNA deregulation event in neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID). Yet, how miR-146a upregulation affects the developing fetal brain remains unclear. Methods: We analyzed the expression of miR-146a in the temporal lobe of ASD children using Taqman assay. To assess the role of miR-146a in early brain development, we generated and characterized stably induced H9 human neural stem cell (H9 hNSC) overexpressing miR-146a using various cell and molecular biology techniques. Results: We first showed that miR-146a upregulation occurs early during childhood in the ASD brain. In H9 hNSC, miR-146a overexpression enhances neurite outgrowth and branching and favors differentiation into neuronal like cells. Expression analyses revealed that 10% of the transcriptome was deregulated and organized into two modules critical for cell cycle control and neuronal differentiation. Twenty known or predicted targets of miR-146a were significantly deregulated in the modules, acting as potential drivers. The two modules also display distinct transcription profiles during human brain development, affecting regions relevant for ASD including the neocortex, amygdala, and hippocampus. Cell type analyses indicate markers for pyramidal, and interneurons are highly enriched in the deregulated gene list. Up to 40% of known markers of newly defined neuronal lineages were deregulated, suggesting that miR-146a could participate also in the acquisition of neuronal identities. Conclusion: Our results demonstrate the dynamic roles of miR-146a in early neuronal development and provide new insight into the molecular events that link miR-146a overexpression to impaired neurodevelopment. This, in turn, may yield new therapeutic targets and strategies. En ligne : https://dx.doi.org/10.1186/s13229-018-0219-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders [texte imprimé] / Lam Son NGUYEN, Auteur ; Julien FREGEAC, Auteur ; Christine BOLE-FEYSOT, Auteur ; Nicolas CAGNARD, Auteur ; Anand IYER, Auteur ; Jasper ANINK, Auteur ; Eleonora ARONICA, Auteur ; Olivier ALIBEU, Auteur ; Patrick NITSCHKÉ, Auteur ; Laurence COLLEAUX, Auteur . - 38p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 38p. Mots-clés : Autism Spectrum Disorder/genetics/metabolism  Cell Line  Cell Lineage  Child  Female  Humans  Male  MicroRNAs/genetics/metabolism  Neural Stem Cells/cytology/metabolism  Neurogenesis  Temporal Lobe/cytology/metabolism  Up-Regulation  Autism spectrum disorders  Human neural stem cell  Transcriptome  microRNA Index. décimale : PER Périodiques Résumé : Background: MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs have emerged as important modulators of brain development and neuronal function and are implicated in several neurological diseases. Previous studies found miR-146a upregulation is the most common miRNA deregulation event in neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID). Yet, how miR-146a upregulation affects the developing fetal brain remains unclear. Methods: We analyzed the expression of miR-146a in the temporal lobe of ASD children using Taqman assay. To assess the role of miR-146a in early brain development, we generated and characterized stably induced H9 human neural stem cell (H9 hNSC) overexpressing miR-146a using various cell and molecular biology techniques. Results: We first showed that miR-146a upregulation occurs early during childhood in the ASD brain. In H9 hNSC, miR-146a overexpression enhances neurite outgrowth and branching and favors differentiation into neuronal like cells. Expression analyses revealed that 10% of the transcriptome was deregulated and organized into two modules critical for cell cycle control and neuronal differentiation. Twenty known or predicted targets of miR-146a were significantly deregulated in the modules, acting as potential drivers. The two modules also display distinct transcription profiles during human brain development, affecting regions relevant for ASD including the neocortex, amygdala, and hippocampus. Cell type analyses indicate markers for pyramidal, and interneurons are highly enriched in the deregulated gene list. Up to 40% of known markers of newly defined neuronal lineages were deregulated, suggesting that miR-146a could participate also in the acquisition of neuronal identities. Conclusion: Our results demonstrate the dynamic roles of miR-146a in early neuronal development and provide new insight into the molecular events that link miR-146a overexpression to impaired neurodevelopment. This, in turn, may yield new therapeutic targets and strategies. En ligne : https://dx.doi.org/10.1186/s13229-018-0219-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

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