Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention

Karen Yap, Zhao Qin Lim, Piyush Khandelia, Brad Friedman, Evgeniy Makeyev

Research output: Contribution to journalArticlepeer-review

207 Citations (Scopus)

Abstract

Differentiated cells acquire unique structural and functional traits through coordinated expression of lineage-specific genes. An extensive battery of genes encoding components of the synaptic transmission machinery and specialized cytoskeletal proteins is activated during neurogenesis, but the underlying regulation is not well understood. Here we show that genes encoding critical presynaptic proteins are transcribed at a detectable level in both neurons and nonneuronal cells. However, in nonneuronal cells, the splicing of 3'-terminal introns within these genes is repressed by the polypyrimidine tract-binding protein (Ptbp1). This inhibits the export of incompletely spliced mRNAs to the cytoplasm and triggers their nuclear degradation. Clearance of these intron-containing transcripts occurs independently of the nonsense-mediated decay (NMD) pathway but requires components of the nuclear RNA surveillance machinery, including the nuclear pore-associated protein Tpr and the exosome complex. When Ptbp1 expression decreases during neuronal differentiation, the regulated introns are spliced out, thus allowing the accumulation of translation-competent mRNAs in the cytoplasm. We propose that this mechanism counters ectopic and precocious expression of functionally linked neuron-specific genes and ensures their coherent activation in the appropriate developmental context.

Original languageEnglish
Pages (from-to)1209-1223
Number of pages15
JournalGenes and Development
Volume26
Issue number11
DOIs
Publication statusPublished - Jun 2012

Keywords

  • coordinated gene expression
  • neuronal differentiation
  • presynaptic proteins
  • polypyrimidine tract-binding protein
  • intron retention
  • nuclear mRNA surveillance
  • NUCLEAR RETENTION
  • HUMAN TRANSCRIPTOME
  • SPLICING REGULATION
  • MAMMALIAN-CELLS
  • FISSION YEAST
  • PROTEIN
  • PTB
  • DEGRADATION
  • EXPRESSION
  • NONSENSE

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