Change of Guards: ELAVL Proteins Switch miRNA Export Responsibility to Regulate Neuronal Differentiation

ELAVL1 protein HuR controls the stability and activity of miRNAs by disconnecting miRNPs from their target mRNAs and exporting Ago2-uncoupled miRNAs to help hepatic and macrophage cells manage stress. In mammalian neurons, the homolog of HuR, ELAVL4 or HuD, is expressed; however, its role in miRNA regulation remains unknown. PC12, a rat pheochromocytoma cell line, is a well-established model for studying neuronal differentiation that resembles sympathetic neurons. In PC12 cells, HuD levels increase during differentiation, which suppresses HuR expression. Thus, HuD overrides HuR’s control of miRNA activity in differentiating cells, promoting differentiation by regulating the activity and levels of specific miRNAs, such as let-7a and miR-125b. When HuD is present, it decreases the activity of these miRNAs by binding to them, thereby facilitating their export and ensuring neuronal differentiation. Overall, there is a shift in miRNA regulation, with HuR being replaced by HuD in controlling miRNA export during neuronal differentiation. This switch in ELAVL-mediated miRNA regulation is essential for the differentiation process.