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

Mol Cell. 2007 Aug 3;27(3):435-48. doi: 10.1016/j.molcel.2007.07.015.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • 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 Precursors / genetics
  • RNA Precursors / metabolism*
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism*
  • Transfection

Substances

  • Heterogeneous-Nuclear Ribonucleoproteins
  • MIRN124 microRNA, human
  • MicroRNAs
  • Nerve Tissue Proteins
  • PTBP1 protein, human
  • Ptbp2 protein, mouse
  • RNA Precursors
  • RNA, Messenger
  • Polypyrimidine Tract-Binding Protein

Associated data

  • GEO/GSE8498