MicroRNAs (miRNAs) are important regulators of neuronal development, network connectivity, and synaptic plasticity. While many neuronal miRNAs were previously shown to modulate neuronal ...morphogenesis, little is known regarding the regulation of miRNA function. In a large‐scale functional screen, we identified two novel regulators of neuronal miRNA function, Nova1 and Ncoa3. Both proteins are expressed in the nucleus and the cytoplasm of developing hippocampal neurons. We found that Nova1 and Ncoa3 stimulate miRNA function by different mechanisms that converge on Argonaute (Ago) proteins, core components of the miRNA‐induced silencing complex (miRISC). While Nova1 physically interacts with Ago proteins, Ncoa3 selectively promotes the expression of Ago2 at the transcriptional level. We further show that Ncoa3 regulates dendritic complexity and dendritic spine maturation of hippocampal neurons in a miRNA‐dependent fashion. Importantly, both the loss of miRNA activity and increased dendrite complexity upon Ncoa3 knockdown were rescued by Ago2 overexpression. Together, we uncovered two novel factors that control neuronal miRISC function at the level of Ago proteins, with possible implications for the regulation of synapse development and plasticity.
Synopsis
The identification of two novel modulators of miRNA function reveals an additional layer of transcriptional and post‐transcriptional control of Argonaute proteins and adds further insight on the central role for miRNAs in neurogenesis.
Large‐scale RNAi screen identifies novel miRNA regulatory proteins in primary neurons.
Ncoa3 and Nova1 are required for the repressive activity of the spine‐regulating miR‐134.
Nova1 is a general, miRISC‐associated miRNA regulatory RBP in neurons.
Ncoa3 regulates a specific subset of miRNA target interactions involved in the control of dendritogenesis.
Ncoa3‐dependent transcriptional regulation of the miRISC protein Ago2 is required for the control of miRNA activity and dendritogenesis.
The identification of two novel modulators of miRNA function reveals an additional layer of transcriptional and post‐transcriptional control of Argonaute proteins and adds further insight on the central role for miRNAs in neurogenesis.
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