The MicroRNA miR-124 Promotes Neuronal Differentiation by Triggering Brain-Specific Alternative Pre-mRNA Splicing

• Published in: Molecular cell Vol. 27; no. 3; pp. 435 - 448
• Main Authors: Makeyev, Eugene V., Zhang, Jiangwen, Carrasco, Monica A., Maniatis, Tom
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.08.2007
• Subjects: Alternative Splicing - genetics; Animals; Brain - physiology; Cell Differentiation; Cells, Cultured; Exons; Gene Expression Regulation, Developmental; Heterogeneous-Nuclear Ribonucleoproteins - genetics; Heterogeneous-Nuclear Ribonucleoproteins - metabolism; Humans; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Mitosis - physiology; MOLNEURO; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neurons - cytology; Neurons - metabolism; Polypyrimidine Tract-Binding Protein - genetics; Polypyrimidine Tract-Binding Protein - metabolism; RNA; RNA Precursors - genetics; RNA Precursors - metabolism; RNA Processing, Post-Transcriptional; RNA, Messenger - chemistry; RNA, Messenger - metabolism; Transfection; RNA; MOLNEURO
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2007.07.015

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.