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A MicroRNA Upregulates Neuron‐Specific Transcripts through the NMD Pathway
Author(s) -
Wilkinson Miles Frome,
Huang Lulu,
Bhalla Angela D,
Bhardwaj Anjana,
Song HyeWon,
Karam Rachid,
Bruno Ivone G
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.498.2
Subject(s) - biology , microrna , microbiology and biotechnology , rna , downregulation and upregulation , regulator , nonsense mediated decay , rna splicing , embryonic stem cell , regulation of gene expression , gene , genetics
Cells are equipped with multiple RNA regulatory mechanisms that control the expression of specific proteins. Here we report that an miRNA expressed selectively in the brain, miR‐128, regulates another RNA‐repressing mechanism: nonsense‐mediated decay (NMD). miR‐128 directly regulates two NMD factors: the RNA helicase UPF1 and the exon junction complex core component MLN51. Gain‐of‐function and loss‐of‐function experiments demonstrated that miR‐128 downregulates the magnitude of NMD, and rescue experiments provided evidence that miR‐128 has this effect by acting through both UPF1 and MLN51. The level of miR‐ 128 dramatically increases in precursor neural cells induced to differentiate in vitro and during embryonic brain development in vivo . Because miR‐128 inhibits NMD, which itself inhibits RNA expression, we hypothesized that the rise in miR‐128 levels during brain development serves to upregulate transcripts with features recognized by the NMD pathway. Supporting this hypothesis, we found that miR‐128 increased the levels of many neuronal transcripts regulated by NMD, including those encoding the neuron‐specific RNA splicing regulator nPTP and the synaptic regulator ARC. Forced miR‐128 expression in either a stem cell line or primary neuronal stem cells upregulated several neuronal differentiation markers, suggesting that miR‐128 promotes neuron differentiation. Together, our results suggest the existence of interconnected RNA circuitry between the miRNA and NMD pathways, which provides a novel means to induce cell type‐ specific gene expression during development.