Abstract
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 ARPP21 recognition of uridine-rich sequences with high specificity for 3′UTRs. ARPP21 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 ARPP21 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 ARPP21 reduces dendritic complexity; ectopic ARPP21 leads to an increase. Thus, we describe a unique example of convergent function by two products of a single gene.
Highlights
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
Using individual-nucleotide resolution crosslinking and immunoprecipitation to characterize mRNA substrates for ARPP21, we found that ARPP21 preferentially binds to uridine-rich sequences in the 3′ untranslated region (UTR) of mRNAs
A variety of regulatory interactions between miRNAs and RNA-binding proteins (RBPs) are known to occur within the 3′UTR sequences of mRNAs
Summary
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. Protein–protein interaction data and functional assays suggest that ARPP21 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 ARPP21 reduces dendritic complexity; ectopic ARPP21 leads to an increase. Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany These authors contributed : Daniel Maticzka, Sabine Grosser, Pina Knauff. Multiple mechanisms act at the post-transcriptional level to enable the dynamic adjustment of gene expression; an ability critical to the correct specification and differentiation of cell types during development. During cortex development miR-128 inhibits migration and limits dendritic growth and complexity of upper-layer neurons[6]. A better understanding of how miR-128 activity is regulated would provide insight into how miR-128 can perform its multiple developmental functions
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