Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders
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ABSTRACT:
PROVIDER: PRJNA392463 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5784070_1.fastq.gz | Fastqsanger.gz | |||
| SRR5784070_2.fastq.gz | Fastqsanger.gz | |||
| SRR5784071_1.fastq.gz | Fastqsanger.gz | |||
| SRR5784071_2.fastq.gz | Fastqsanger.gz | |||
| SRR5784072_1.fastq.gz | Fastqsanger.gz |
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Project description: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 disorders (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 ten percent 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 miR146a overexpression to impaired neurodevelopment. This, in turn, may yield new therapeutic targets and strategies.
2018-06-27 | GSE100670 | GEO
Project description:MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression post-transcriptionally. miRs are involved in a wide range of regulation networks, including those involved in brain development. We and other showed an upregulation of miR-146a in autism spectrum disorders, intellectual disability and epilepsy. Taking advantage of a mouse model constitutively inactivated for miR-146a, we investigated its functions during brain development using a combination of imaging, molecular, cell biology techniques and behavioral studies. We demonstrated that loss of miR-146a causes time and region specific expression defects in the mouse brain. Pyramidal and interneurons are the most severely affected cell types with deregulated pathways reflecting different stages of neuronal differentiation and synaptic maturation. We showed that absence of miR-146a impairs the balance between proliferation and differentiation of neural progenitors. We observed no difference in neither brain weight nor total volume but an increased hemispheric asymmetry of hippocampal volume. Lastly, impaired associative memory was also observed. Our results show that miR-146 is important for proper brain development and support the hypothesis that miR-146a deregulation may play a role in developmental brain disorders.
2019-06-01 | GSE114491 | GEO
Project description:BackgroundMicroRNAs (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.MethodsWe 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.ResultsWe 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.ConclusionOur 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.
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Project description:Role of miR-146a in mouse brain development: relevance for developmental brain disorders
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Project description:<p><strong>Background: </strong>Selective serotonin reuptake inhibitors (SSRIs) are often prescribed during pregnancy. Yet, epidemiological studies link in-utero SSRI exposure with neurodevelopmental disorders, such as autism and ADHD. The potential molecular mechanisms by which SSRIs impact early neurodevelopment are not fully understood.</p><p> </p><p><strong>Methods:</strong> We exposed neuroepithelial stem cells derived from four human induced pluripotent stem cells lines to fluoxetine, citalopram, sertraline, and paroxetine. We then assessed cellular viability, reactive oxygen species (ROS) levels, mitochondrial function using adenosine triphosphate (ATP) assays, and performed high-throughput metabolomics at two timepoints: proliferation and neural differentiation stages. The key metabolic findings were validated in the in-vitro model and in a complementary population-based cohort, the Barwon Infant Study, consisting of 1074 mother-child pairs with analysed cord-blood metabolomes.</p><p> </p><p><strong>Findings:</strong> Sertraline and paroxetine significantly decreased ROS and ATP levels, indicating mitochondrial alteration. Metabolomic profiling revealed consistent elevation of three lysophosphatidylcholines (LPCs 16:0, 18:0, 18:1) across all SSRIs except citalopram. We further observed elevated LPC levels in the cord blood of infants prenatally exposed to SSRIs, with a dose-dependent correlation to autism and ADHD-related symptoms at age two. Furthermore, the three LPCs modulated ROS and ATP levels in the neural cells.</p><p> </p><p><strong>Interpretation:</strong> These findings provide insights into SSRI-induced molecular changes, highlight candidate metabolites that may warrant further investigation as indicators of SSRI exposure, and emphasise the need for exploring prenatal SSRI exposure effects and neurodevelopmental outcomes.</p>
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Project description:Disrupted in schizophrenia 1 (DISC1) has been implicated in contributing to a number of psychiatric diseases and neurodevelopmental phenotypes such as the proliferation and differentiation of neural progenitor cells. While there has been significant effort directed towards understanding the function of DISC1 through the determination of its protein-protein interactions within an in-vitro setting, endogenous interactions involving DISC1 within a cell-type specific setting relevant to neural development remain unclear.
2018-07-04 | PXD007103 | Pride
Project description:Heterozygous de novo missense mutations in genes encoding Polycomb-group (PcG) proteins can cause diverse neurodevelopmental disorders (NDDs), but the underlying mechanisms are not yet understood. Here, we identified novel mutations in the two E3-ligases of the Polycomb Repressive complex 1 (PRC1), RING1 and RNF2, in individuals with NDDs and uncover distinct mechanisms by which PRC1 activity can be compromised. As a proof of concept, we generated embryonic stem cells (ESCs) and a novel mouse model carrying a heterozygous Rnf2 allele with a missense mutation that produces a deleterious Ring1bR70H variant. This variant causes a cell fate change in neuroprecursors (NPCs) towards the non-neuronal lineages glial and microglia. Allele-specific profiling revealed that Ring1bR70H integrates into canonical PRC1 and displaces variant PRC1 from chromatin. As a result, there is a disruption of the PRC1 balance and a deregulation of PcG target genes. We uncovered that mutant NPCs have an aberrant PcG retention and chromatin compaction pattern at key NPC pioneer factors and Wnt signaling genes. Critically, this heterozygous Rnf2 mutation in mice is sufficient to disrupt neural connectivity and structural organization in key brain regions, including the medial prefrontal cortex and hippocampus. Our findings establish Rnf2 as essential for neurodevelopmental integrity and brain function, shedding light on how PRC1 dysfunction contributes to NDDs.
2026-04-06 | PXD059191 | Pride
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Project description:Mice experiment for GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders
2024-04-15 | E-MTAB-13477 | biostudies-arrayexpress