Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention.
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.
School of Biological Sciences, Nanyang Technological University, Singapore.
Karen
K
Yap
Zhao Qin
ZQ
Lim
Piyush
P
Khandelia
Brad
B
Friedman
Eugene V
EV
Makeyev
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D055354:Exosomes / Q000378:metabolism; D055785:Gene Knockdown Techniques; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D007438:Introns; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012322:RNA Precursors / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*; D022622:Shiga Toxin 1 / Q000235:genetics / Q000378:metabolism; D050827:Syntaxin 1 / Q000235:genetics / Q000378:metabolism
D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D011518:Proto-Oncogene Proteins; C573992:Ptbp1 protein, mouse; D012322:RNA Precursors; D012333:RNA, Messenger; D022622:Shiga Toxin 1; D050827:Syntaxin 1; C573993:TPR protein, mouse; D038941:Polypyrimidine Tract-Binding Protein