The RNA-binding protein ARPP21 controls dendritic branching by functionally opposing the miRNA it hosts.

About half of mammalian miRNA genes lie within introns of protein-coding genes, yet little is known about functional interactions between miRNAs and their host genes. The intronic miRNA miR-128 regulates neuronal excitability and dendritic morphology of principal neurons during mouse cerebral cortex development. Its conserved host genes, R3hdm1 and Arpp21, are predicted RNA-binding proteins. Here we use iCLIP to characterize recognition of uridine-rich sequences with high specificity for 3'UTRs. duanyu37P21 antagonizes miR-128 activity by co-regulating a subset of miR-128 target mRNAs enriched for neurodevelopmental functions. Protein-protein interaction data and functional assays suggest that duanyu37P21 acts as a positive post-transcriptional regulator by interacting with the translation initiation complex eIF4F. This molecular antagonism is reflected in inverse activities during dendritogenesis: miR-128 overexpression or knockdown of duanyu37P21 reduces dendritic complexity; ectopic duanyu37P21 leads to an increase. Thus, we describe a unique example of convergent function by two products of a single gene.

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