title: A post-transcriptional mechanism pacing expression of neural genes with precursor cell differentiation status.
abstract: Nervous system (NS) development relies on coherent upregulation of extensive sets of genes in a precise spatiotemporal manner. How such transcriptome-wide effects are orchestrated at the molecular level remains an open question. Here we show that 3'-untranslated regions (3' UTRs) of multiple neural transcripts contain AU-rich cis-elements (AREs) recognized by tristetraprolin (TTP/Zfp36), an RNA-binding protein previously implicated in regulation of mRNA stability. We further demonstrate that the efficiency of ARE-dependent mRNA degradation declines in the neural lineage because of a decrease in the TTP protein expression mediated by the NS-enriched microRNA miR-9. Importantly, TTP downregulation in this context is essential for proper neuronal differentiation. On the other hand, inactivation of TTP in non-neuronal cells leads to dramatic upregulation of multiple NS-specific genes. We conclude that the newly identified miR-9/TTP circuitry limits unscheduled accumulation of neuronal mRNAs in non-neuronal cells and ensures coordinated upregulation of these transcripts in neurons.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Weijun
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Mainul
authors.initials: M
authors.lastname: Hoque
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Zhuyun
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.|MRC Centre for Developmental Neurobiology, King's College London, London SE1 1UL, UK.
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Makeyev
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs; D009474:Neurons / Q000378:metabolism*; D010957:Plasmids; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C551804:MIRN9 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse