The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.
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.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Eugene V
EV
Makeyev
Jiangwen
J
Zhang
Monica A
MA
Carrasco
Tom
T
Maniatis
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005091:Exons; D018507:Gene Expression Regulation, Developmental; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection
D034441:Heterogeneous-Nuclear Ribonucleoproteins; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; C450006:PTBP1 protein, human; C429773:Ptbp2 protein, mouse; D012322:RNA Precursors; D012333:RNA, Messenger; D038941:Polypyrimidine Tract-Binding Protein