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

• Published in: Nature communications 2018-03, Vol.9 (1), p.1235-13, Article 1235
• Main Authors: Rehfeld, Frederick, Maticzka, Daniel, Grosser, Sabine, Knauff, Pina, Eravci, Murat, Vida, Imre, Backofen, Rolf, Wulczyn, F. Gregory
• Format: Article
• Language: English
• Subjects: 13; 13/31; 13/89; 14; 14/19; 3' Untranslated Regions; 38; 38/1; 38/91; 42/35; 42/44; 631/136/142; 631/208/200; 631/337/384/331; 631/378/340; 631/80/83; Animals; Antagonism; Cerebral cortex; Complexity; Cytoplasmic Granules - metabolism; Dendrites - physiology; Dendritic branching; Dendritic structure; Eukaryotic Initiation Factor-4F - metabolism; Excitability; Gene Knockdown Techniques; Genes; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Initiation complex; Introns; Mice; MicroRNAs - genetics; miRNA; multidisciplinary; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphoproteins - physiology; Post-transcription; Protein Interaction Maps; Proteins; Proteolysis; Ribonucleic acid; RNA; RNA Processing, Post-Transcriptional; RNA-binding protein; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; RNA-Binding Proteins - physiology; Science; Science (multidisciplinary); Translation initiation; Uridine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03681-3

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. Many microRNA encoding regions are within introns of other coding genes, and yet the molecular or functional interaction between the two is unclear. This study shows that miR-128′s function is opposed by its host gene ARPP21 , and they have complementary effects on neuronal development.