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Abstract
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.
Highlights
MicroRNAs are small, non-coding RNAs that regulate gene expression at the posttranscriptional level. miRNAs have emerged as important modulators of brain development and neuronal function and are implicated in several neurological diseases
Results miR-146a overexpression occurs early during human brain development autism spectrum disorder (ASD), which is diagnosed before the age of 3, is associated with brain defects arising during early development, including enlarged brain volume (2–5%) that ameliorates in later stages [23] and disorganized cortical layers [24]
Generation and validation H9 Human neural stem cell (hNSC) lines overexpressing miR-146a To elucidate the role of miR-146a in neural development, we used integrating viral approach to establish two H9 human neural stem cell (H9 hNSC) lines stably overexpressing a wild-type miR-146a gene or its mutant form, miR-146a-Mut
Summary
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the posttranscriptional 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). The heritability rate of autism spectrum disorder (ASD) is over 50% with the remaining attributed to environmental/epigenetic factors [1]. MicroRNA (miRNA), one such factor, fine-tunes gene expression required for the development and function of cells and organs. Our group and others implicated upregulation of miR-146a as the most common miRNA deregulation event in ASD [2, 3] and related neurodevelopmental disorders such as epilepsy [4] and intellectual disability (ID) [2]. Understanding the functions of this miRNA in the brain may offer opportunities to develop treatments that are currently not available for neurodevelopmental disorders
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