Global regulation of neuronal transcriptome by miR-9/tristetraprolin circuitry

Nervous system (NS) development relies on coherent up-regulation of extensive sets of genes in a precise spatiotemporal manner. How such transcriptome-wide effects are orchestrated at the molecular level remains an open question. Here we show that 3'-untranslated regions (3'UTRs) of multiple neuronal transcripts contain A/U-rich cis-elements (AREs) recognized by tristetraprolin (TTP/Zfp36), an RNA-binding protein previously reported to destabilize mRNAs encoding predominantly cytokines, growth factors and proto-oncogenes. We further demonstrate that the efficiency of ARE-dependent mRNA degradation declines during neural differentiation due to a decrease in the TTP protein expression mediated by the NS-enriched microRNA miR-9. Our experiments with transgenenic cell lines suggest that TTP down-regulation is essential for proper neuronal differentiation. Moreover, inactivation of TTP in neuroblastoma cells or mouse embryonic fibroblasts induces major changes in their transcriptomes accompanied by significantly elevated expression of NS-specific genes. We conclude that the newly identified miR-9/TTP circuitry limits unscheduled accumulation of neuronal mRNAs in non-neuronal cells and ensures coordinated up-regulation of these transcripts in neurons. Overall design: 3''READS of undifferentiated and 3.5-day differentiated P19 cells