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      The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.

      Molecular Cell

      Alternative Splicing, genetics, Animals, Brain, physiology, Cell Differentiation, Cells, Cultured, Exons, Gene Expression Regulation, Developmental, Heterogeneous-Nuclear Ribonucleoproteins, metabolism, Humans, Mice, MicroRNAs, Mitosis, Nerve Tissue Proteins, Neuroblastoma, pathology, Neurons, cytology, Polypyrimidine Tract-Binding Protein, RNA Precursors, RNA Processing, Post-Transcriptional, RNA, Messenger, chemistry, Transfection

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          Abstract

          Both microRNAs and alternative pre-mRNA splicing have been implicated in the development of the nervous system (NS), but functional interactions between these two pathways are poorly understood. We demonstrate that the neuron-specific microRNA miR-124 directly targets PTBP1 (PTB/hnRNP I) mRNA, which encodes a global repressor of alternative pre-mRNA splicing in nonneuronal cells. Among the targets of PTBP1 is a critical cassette exon in the pre-mRNA of PTBP2 (nPTB/brPTB/PTBLP), an NS-enriched PTBP1 homolog. When this exon is skipped, PTBP2 mRNA is subject to nonsense-mediated decay (NMD). During neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. These events culminate in the transition from non-NS to NS-specific alternative splicing patterns. We also present evidence that miR-124 plays a key role in the differentiation of progenitor cells to mature neurons. Thus, miR-124 promotes NS development, at least in part by regulating an intricate network of NS-specific alternative splicing.

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          Author and article information

          Journal
          17679093
          3139456
          10.1016/j.molcel.2007.07.015

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