Change of guards: ELAVL proteins switch miRNA export responsibility to regulate differentiation of PC12 cells

In the rat pheochromocytoma cell line PC12, which resembles sympathetic neurons, miRNA activity decreases during differentiation, and inactivation of the let-7a miRNP is essential for differentiation. We sought to examine how let-7a activity is affected during differentiation. Extracellular vesicle-mediated miRNA export is a common strategy used by mammalian cells to regulate miRNA activity. HuR, an ELAVL protein that influences miRNA stability and activity by exporting Ago2-unbound miRNAs via extracellular vesicles, decreases in differentiating PC12 cells, whereas another ELAVL protein, HuD, increases. We found that HuD expression increases to takes up HuR's role in miRNA export regulation, thereby aiding differentiation by modulating specific miRNAs, such as let-7a and miR-125b. HuD binds these miRNAs, reducing their activity and promoting their export, thereby supporting PC12 differentiation. This switch in miRNA export responsibility from HuR to HuD may be both necessary and sufficient for neuronal differentiation.