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A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders / A. DE SENA CORTABITARTE in Journal of Neurodevelopmental Disorders, 10-1 (December 2018)
[article]
Titre : A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders Type de document : Texte imprimé et/ou numérique Auteurs : A. DE SENA CORTABITARTE, Auteur ; S. BERKEL, Auteur ; F. B. CRISTIAN, Auteur ; C. FISCHER, Auteur ; G. A. RAPPOLD, Auteur Année de publication : 2018 Article en page(s) : 15 p. Langues : Anglais (eng) Mots-clés : Autism Intellectual disability Shank2 Schizophrenia miR-137 microRNA Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the SHANK genes, which encode postsynaptic scaffolding proteins, have been linked to a spectrum of neurodevelopmental disorders. The SHANK genes and the schizophrenia-associated microRNA-137 show convergence on several levels, as they are both expressed at the synapse, influence neuronal development, and have a strong link to neurodevelopmental and neuropsychiatric disorders like intellectual disability, autism, and schizophrenia. This compiled evidence raised the question if the SHANKs might be targets of miR-137. METHODS: In silico analysis revealed a putative binding site for microRNA-137 (miR-137) in the SHANK2 3'UTR, while this was not the case for SHANK1 and SHANK3. Luciferase reporter assays were performed by overexpressing wild type and mutated SHANK2-3'UTR and miR-137 in human neuroblastoma cells and mouse primary hippocampal neurons. miR-137 was also overexpressed or inhibited in hippocampal neurons, and Shank2 expression was analyzed by quantitative real-time PCR and Western blot. Additionally, expression levels of experimentally validated miR-137 target genes were analyzed in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control individuals using the RNA-Seq data from the CommonMind Consortium. RESULTS: miR-137 directly targets the 3'UTR of SHANK2 in a site-specific manner. Overexpression of miR-137 in mouse primary hippocampal neurons significantly lowered endogenous Shank2 protein levels without detectable influence on mRNA levels. Conversely, miR-137 inhibition increased Shank2 protein expression, indicating that miR-137 regulates SHANK2 expression by repressing protein translation rather than inducing mRNA degradation. To find out if the miR-137 signaling network is altered in schizophrenia, we compared miR-137 precursor and miR-137 target gene expression in the DLPFC of schizophrenia and control individuals using the CommonMind Consortium RNA sequencing data. Differential expression of 23% (16/69) of known miR-137 target genes was detected in the DLPFC of schizophrenia individuals compared with controls. We propose that in further targets (e.g., SHANK2, as described in this paper) which are not regulated on RNA level, effects may only be detectable on protein level. CONCLUSION: Our study provides evidence that a direct regulatory link exists between miR-137 and SHANK2 and supports the finding that miR-137 signaling might be altered in schizophrenia. En ligne : http://dx.doi.org/10.1186/s11689-018-9233-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386
in Journal of Neurodevelopmental Disorders > 10-1 (December 2018) . - 15 p.[article] A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders [Texte imprimé et/ou numérique] / A. DE SENA CORTABITARTE, Auteur ; S. BERKEL, Auteur ; F. B. CRISTIAN, Auteur ; C. FISCHER, Auteur ; G. A. RAPPOLD, Auteur . - 2018 . - 15 p.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 10-1 (December 2018) . - 15 p.
Mots-clés : Autism Intellectual disability Shank2 Schizophrenia miR-137 microRNA Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the SHANK genes, which encode postsynaptic scaffolding proteins, have been linked to a spectrum of neurodevelopmental disorders. The SHANK genes and the schizophrenia-associated microRNA-137 show convergence on several levels, as they are both expressed at the synapse, influence neuronal development, and have a strong link to neurodevelopmental and neuropsychiatric disorders like intellectual disability, autism, and schizophrenia. This compiled evidence raised the question if the SHANKs might be targets of miR-137. METHODS: In silico analysis revealed a putative binding site for microRNA-137 (miR-137) in the SHANK2 3'UTR, while this was not the case for SHANK1 and SHANK3. Luciferase reporter assays were performed by overexpressing wild type and mutated SHANK2-3'UTR and miR-137 in human neuroblastoma cells and mouse primary hippocampal neurons. miR-137 was also overexpressed or inhibited in hippocampal neurons, and Shank2 expression was analyzed by quantitative real-time PCR and Western blot. Additionally, expression levels of experimentally validated miR-137 target genes were analyzed in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control individuals using the RNA-Seq data from the CommonMind Consortium. RESULTS: miR-137 directly targets the 3'UTR of SHANK2 in a site-specific manner. Overexpression of miR-137 in mouse primary hippocampal neurons significantly lowered endogenous Shank2 protein levels without detectable influence on mRNA levels. Conversely, miR-137 inhibition increased Shank2 protein expression, indicating that miR-137 regulates SHANK2 expression by repressing protein translation rather than inducing mRNA degradation. To find out if the miR-137 signaling network is altered in schizophrenia, we compared miR-137 precursor and miR-137 target gene expression in the DLPFC of schizophrenia and control individuals using the CommonMind Consortium RNA sequencing data. Differential expression of 23% (16/69) of known miR-137 target genes was detected in the DLPFC of schizophrenia individuals compared with controls. We propose that in further targets (e.g., SHANK2, as described in this paper) which are not regulated on RNA level, effects may only be detectable on protein level. CONCLUSION: Our study provides evidence that a direct regulatory link exists between miR-137 and SHANK2 and supports the finding that miR-137 signaling might be altered in schizophrenia. En ligne : http://dx.doi.org/10.1186/s11689-018-9233-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386 Longitudinal stability of salivary microRNA biomarkers in children and adolescents with autism spectrum disorder / David LEVITSKIY in Research in Autism Spectrum Disorders, 85 (July 2021)
[article]
Titre : Longitudinal stability of salivary microRNA biomarkers in children and adolescents with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : David LEVITSKIY, Auteur ; Alexandra CONFAIR, Auteur ; Kayla E. WAGNER, Auteur ; Samantha DEVITA, Auteur ; Nicole SHEA, Auteur ; Elizabeth P. MCKERNAN, Auteur ; Justin KOPEC, Auteur ; Natalie RUSSO, Auteur ; Frank A. MIDDLETON, Auteur ; Steven D. HICKS, Auteur Article en page(s) : 101788 Langues : Anglais (eng) Mots-clés : Prognosis Biomarkers Saliva RNA microRNA Autism Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorder (ASD) is a complex neurological condition with increasing prevalence. Few tools accurately predict the developmental trajectory of children with ASD. Such tools would allow clinicians to provide accurate prognoses and track the efficacy of therapeutic interventions. Salivary RNAs that reflect the genetic-environmental interactions underlying ASD may provide objective measures of symptom severity and developmental outcomes. This study investigated whether salivary RNAs previously identified in childhood ASD remain perturbed in older children. We also explored whether RNA candidates changed with therapeutic intervention. Method A case-control design was used to characterize levels of 78 saliva RNA candidates among 96 children (48 ASD, 48 non-ASD, mean age: 11 years). Thirty-one children (22 ASD, 9 non-ASD developmental delay, mean age: 4 years) were followed longitudinally to explore changes of RNA candidates during early intervention. Saliva RNA and standardized behavioral assessments were collected for each participant. Associations between candidate RNAs and behavioral scores were determined in both groups via Spearman Correlation. Changes in candidate RNAs across two time-points were assessed in the younger cohort via Wilcoxon rank-sum test. Results Seven RNAs were associated with VABS-II and BASC scores in the older group ([R] >0.25, FDR?0.15). Within the younger cohort, 12 RNAs displayed significant changes over time (FDR?0.05). Three microRNAs were associated with behavioral scores and changed over time (miR-182?5p, miR-146b-5p, miR-374a-5p). Conclusion Several salivary RNAs are strongly associated with autistic behaviors in older individuals with ASD and change as early as three months after therapy initiation in younger children. These molecules could be used to track treatment effectiveness and provide prognoses. Further validation is necessary. En ligne : https://doi.org/10.1016/j.rasd.2021.101788 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=458
in Research in Autism Spectrum Disorders > 85 (July 2021) . - 101788[article] Longitudinal stability of salivary microRNA biomarkers in children and adolescents with autism spectrum disorder [Texte imprimé et/ou numérique] / David LEVITSKIY, Auteur ; Alexandra CONFAIR, Auteur ; Kayla E. WAGNER, Auteur ; Samantha DEVITA, Auteur ; Nicole SHEA, Auteur ; Elizabeth P. MCKERNAN, Auteur ; Justin KOPEC, Auteur ; Natalie RUSSO, Auteur ; Frank A. MIDDLETON, Auteur ; Steven D. HICKS, Auteur . - 101788.
Langues : Anglais (eng)
in Research in Autism Spectrum Disorders > 85 (July 2021) . - 101788
Mots-clés : Prognosis Biomarkers Saliva RNA microRNA Autism Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorder (ASD) is a complex neurological condition with increasing prevalence. Few tools accurately predict the developmental trajectory of children with ASD. Such tools would allow clinicians to provide accurate prognoses and track the efficacy of therapeutic interventions. Salivary RNAs that reflect the genetic-environmental interactions underlying ASD may provide objective measures of symptom severity and developmental outcomes. This study investigated whether salivary RNAs previously identified in childhood ASD remain perturbed in older children. We also explored whether RNA candidates changed with therapeutic intervention. Method A case-control design was used to characterize levels of 78 saliva RNA candidates among 96 children (48 ASD, 48 non-ASD, mean age: 11 years). Thirty-one children (22 ASD, 9 non-ASD developmental delay, mean age: 4 years) were followed longitudinally to explore changes of RNA candidates during early intervention. Saliva RNA and standardized behavioral assessments were collected for each participant. Associations between candidate RNAs and behavioral scores were determined in both groups via Spearman Correlation. Changes in candidate RNAs across two time-points were assessed in the younger cohort via Wilcoxon rank-sum test. Results Seven RNAs were associated with VABS-II and BASC scores in the older group ([R] >0.25, FDR?0.15). Within the younger cohort, 12 RNAs displayed significant changes over time (FDR?0.05). Three microRNAs were associated with behavioral scores and changed over time (miR-182?5p, miR-146b-5p, miR-374a-5p). Conclusion Several salivary RNAs are strongly associated with autistic behaviors in older individuals with ASD and change as early as three months after therapy initiation in younger children. These molecules could be used to track treatment effectiveness and provide prognoses. Further validation is necessary. En ligne : https://doi.org/10.1016/j.rasd.2021.101788 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=458 MicroRNAs as biomarkers for psychiatric disorders with a focus on autism spectrum disorder: Current progress in genetic association studies, expression profiling, and translational research / Yubin HU in Autism Research, 10-7 (July 2017)
[article]
Titre : MicroRNAs as biomarkers for psychiatric disorders with a focus on autism spectrum disorder: Current progress in genetic association studies, expression profiling, and translational research Type de document : Texte imprimé et/ou numérique Auteurs : Yubin HU, Auteur ; Erik A. EHLI, Auteur ; Dorret I. BOOMSMA, Auteur Article en page(s) : p.1184-1203 Langues : Anglais (eng) Mots-clés : microRNA miRNA psychiatric disorders autism spectrum disorder biomarkers genetic variation expression profiling animal studies Index. décimale : PER Périodiques Résumé : MicroRNAs (miRNAs) are a group of small noncoding RNA molecules, 18–25 nucleotides in length, which can negatively regulate gene expression at the post-transcriptional level by binding to messenger RNAs. About half of all identified miRNAs in humans are expressed in the brain and display regulatory functions important for many biological processes related to the development of the central nervous system (CNS). Disruptions in miRNA biogenesis and miRNA-target interaction have been related to CNS diseases, including psychiatric disorders. In this review, we focus on the role of miRNAs in autism spectrum disorder (ASD) and summarize recent findings about ASD-associated genetic variants in miRNA genes, in miRNA biogenesis genes, and miRNA targets. We discuss deregulation of miRNA expression in ASD and functional validation of ASD-related miRNAs in animal models. Including miRNAs in studies of ASD will contribute to our understanding of its etiology and pathogenesis and facilitate the discrimination between different disease subgroups. En ligne : http://dx.doi.org/10.1002/aur.1789 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=309
in Autism Research > 10-7 (July 2017) . - p.1184-1203[article] MicroRNAs as biomarkers for psychiatric disorders with a focus on autism spectrum disorder: Current progress in genetic association studies, expression profiling, and translational research [Texte imprimé et/ou numérique] / Yubin HU, Auteur ; Erik A. EHLI, Auteur ; Dorret I. BOOMSMA, Auteur . - p.1184-1203.
Langues : Anglais (eng)
in Autism Research > 10-7 (July 2017) . - p.1184-1203
Mots-clés : microRNA miRNA psychiatric disorders autism spectrum disorder biomarkers genetic variation expression profiling animal studies Index. décimale : PER Périodiques Résumé : MicroRNAs (miRNAs) are a group of small noncoding RNA molecules, 18–25 nucleotides in length, which can negatively regulate gene expression at the post-transcriptional level by binding to messenger RNAs. About half of all identified miRNAs in humans are expressed in the brain and display regulatory functions important for many biological processes related to the development of the central nervous system (CNS). Disruptions in miRNA biogenesis and miRNA-target interaction have been related to CNS diseases, including psychiatric disorders. In this review, we focus on the role of miRNAs in autism spectrum disorder (ASD) and summarize recent findings about ASD-associated genetic variants in miRNA genes, in miRNA biogenesis genes, and miRNA targets. We discuss deregulation of miRNA expression in ASD and functional validation of ASD-related miRNAs in animal models. Including miRNAs in studies of ASD will contribute to our understanding of its etiology and pathogenesis and facilitate the discrimination between different disease subgroups. En ligne : http://dx.doi.org/10.1002/aur.1789 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=309 Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain / Y. HARA in Molecular Autism, 8 (2017)
[article]
Titre : Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain Type de document : Texte imprimé et/ou numérique Auteurs : Y. HARA, Auteur ; Yukio AGO, Auteur ; E. TAKANO, Auteur ; S. HASEBE, Auteur ; T. NAKAZAWA, Auteur ; H. HASHIMOTO, Auteur ; T. MATSUDA, Auteur ; K. TAKUMA, Auteur Article en page(s) : 33p. Langues : Anglais (eng) Mots-clés : Autism mouse model Embryonic brain MicroRNA Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain. RESULTS: Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain. CONCLUSIONS: These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure. En ligne : http://dx.doi.org/10.1186/s13229-017-0149-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330
in Molecular Autism > 8 (2017) . - 33p.[article] Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain [Texte imprimé et/ou numérique] / Y. HARA, Auteur ; Yukio AGO, Auteur ; E. TAKANO, Auteur ; S. HASEBE, Auteur ; T. NAKAZAWA, Auteur ; H. HASHIMOTO, Auteur ; T. MATSUDA, Auteur ; K. TAKUMA, Auteur . - 33p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 33p.
Mots-clés : Autism mouse model Embryonic brain MicroRNA Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain. RESULTS: Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain. CONCLUSIONS: These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure. En ligne : http://dx.doi.org/10.1186/s13229-017-0149-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology / L. S. NGUYEN in Molecular Autism, 7 (2016)
[article]
Titre : Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology Type de document : Texte imprimé et/ou numérique Auteurs : L. S. NGUYEN, Auteur ; M. LEPLEUX, Auteur ; M. MAKHLOUF, Auteur ; C. MARTIN, Auteur ; J. FREGEAC, Auteur ; K. SIQUIER-PERNET, Auteur ; A. PHILIPPE, Auteur ; F. FERON, Auteur ; B. GEPNER, Auteur ; C. ROUGEULLE, Auteur ; Y. HUMEAU, Auteur ; L. 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
in Molecular Autism > 7 (2016) . - 1p.[article] Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology [Texte imprimé et/ou numérique] / L. S. NGUYEN, Auteur ; M. LEPLEUX, Auteur ; M. MAKHLOUF, Auteur ; C. MARTIN, Auteur ; J. FREGEAC, Auteur ; K. SIQUIER-PERNET, Auteur ; A. PHILIPPE, Auteur ; F. FERON, Auteur ; B. GEPNER, Auteur ; C. ROUGEULLE, Auteur ; Y. HUMEAU, Auteur ; L. 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 / L. S. NGUYEN in Molecular Autism, 9 (2018)
PermalinkLoss 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)
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