Mechanisms governing post-transcriptional regulation of neuronal microRNAs

PROJECT SUMMARY Many aspects of neural plasticity require changes in gene expression, either by altering transcription in the nucleus or by targeting RNA molecules post-transcriptionally. Post-transcriptional regulation may be particularly important for allowing neurons to regulate protein production in a rapid and compartment-specific manner. MicroRNAs (miRNAs) influence post-transcriptional gene expression by targeting mRNA molecules for translational repression and degradation and are known to influence neural development and function. A growing body of evidence also suggests that post-transcriptional regulation of miRNAs contributes to experience-dependent synaptic plasticity. However, much remains unknown about the post-transcriptional mechanisms that control miRNA expression. One such mechanism is target-directed miRNA degradation (TDMD), a phenomenon in which trigger RNA molecules direct the degradation of specific miRNA molecules. It was recently shown that TDMD in mammals is mediated by the ZSWIM8 ubiquitin ligase. Preliminary data indicate that dozens of miRNAs are ZSWIM8 sensitive in the mammalian brain, including several miRNAs that have previously been linked to synaptic plasticity, suggesting that the TDMD pathway is poised to have widespread effects on the nervous system. Mice with altered ZSWIM8 expression also exhibit perturbed expression of many physiologically relevant mRNAs, including genes encoding ion channels and synaptic adhesion molecules, further supporting the hypothesis that TDMD affects neural development and physiology. This proposal will assess how TDMD affects neurobiology by (1) determining how ZSWIM8 influences activity- dependent gene expression; (2) identifying TDMD trigger RNAs that drive miRNA degradation in mouse and human neurons; and (3) establishing how TDMD influences neuronal activity and the morphology and plasticity of dendritic spines. Collectively, this work will expand our understanding of the regulatory pathways controlling neuronal gene expression and their downstream consequences for neural function.