Role of <italic>miR-146a</italic> in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders.

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 <italic>miR-146a</italic> upregulation is the most common miRNA deregulation event in neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID). Yet, how <italic>miR-146a</italic> upregulation affects the developing fetal brain remains unclear. Methods: We analyzed the expression of <italic>miR-146a</italic> in the temporal lobe of ASD children using Taqman assay. To assess the role of <italic>miR-146a</italic> in early brain development, we generated and characterized stably induced H9 human neural stem cell (H9 hNSC) overexpressing <italic>miR-146a</italic> using various cell and molecular biology techniques. Results: We first showed that <italic>miR-146a</italic> upregulation occurs early during childhood in the ASD brain. In H9 hNSC, <italic>miR-146a</italic> 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 <italic>miR-146a</italic> 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 <italic>miR-146a</italic> could participate also in the acquisition of neuronal identities. Conclusion: Our results demonstrate the dynamic roles of <italic>miR-146a</italic> in early neuronal development and provide new insight into the molecular events that link <italic>miR-146a</italic> overexpression to impaired neurodevelopment. This, in turn, may yield new therapeutic targets and strategies. [ABSTRACT FROM AUTHOR]