MiR-142-3p is essential for hematopoiesis and affects cardiac cell fate in zebrafish

Department of Cardiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 08/2012; 425(4):755-61. DOI: 10.1016/j.bbrc.2012.07.148
Source: PubMed


MicroRNAs (miRNAs) play a pivotal role during embryonic development and are required for proper organogenesis, including hematopoiesis. Recent studies suggest that, in the early mesoderm, there is an interaction between the hematopoietic and cardiac lineages. However, whether miRNAs can affect other lineages remains unknown. Therefore, we investigated whether hematopoietic miR-142-3p modulated the mesoderm formation. We report that knockdown (KD) of miR-142-3p, a hematopoietic-specific miRNA, in zebrafish resulted in loss of hematopoiesis during embryonic development. Intriguingly, we observed abnormal cardiac phenotypes and insufficiency of somitegenesis in KD-morphants. In the early developmental stage, a tiny heart, contractile dysfunction in the ventricle, cardiac arrhythmia (e.g. a 2:1 ratio of atrial:ventricular beating), and bradycardia were consistently observed. Histological examination revealed severe hypoplasia of the ventricle and disrupted muscle alignment. To determine the mechanism, we performed DNA microarray analysis. The results revealed that the expression of several mesodermal genes essential for the formation of cardiac and somatic mesoderm, such as no tail, T-box gene 16, mesoderm posterior a, one eye pinhead, and rho-associated, coiled-coil containing protein kinase (Rock2a), were increased in miR-142-3p KD-morphants. The luciferase reporter assay revealed that miR-142-3p repressed luciferase activity on the Rock2a 3'-UTR. The findings of the present study indicate that miR-142-3p plays a critical role in hematopoiesis, cardiogenesis, and somitegenesis in the early stage of mesoderm formation via regulation of Rock2a.

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    • "It has been reported that miR-132-3p is up-regulated after IL-12 treatment, and this up-regulation decreases Stat4 and IFN-γ expression [82]. MiR-142-3p, a hematopoietic-specific miRNA [83], was down-regulated after rIFN-γ1 treatment in our study, and previous studies have shown that down-regulation of miR-142-3p can increase IL-6 expression [84], resulting in CD4+ T cell activation [85] and macrophage differentiation in tumors [86]. IL-6 is a proinflammatory cytokine whose production can be activated by the LPS-induced macrophage response, and IFN-γ is known to prime macrophages to enhance their response to LPS [87], [88]. "
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    ABSTRACT: MicroRNAs are endogenous, small non-coding RNAs approximately 18-26 nucleotides in length that regulate target gene expression at the post-transcription level. Interferon-γ (IFN-γ) is a Th1 cytokine that is involved in both the innate and adaptive immune responses. We previously identified two IFN-γ genes in green-spotted puffer fish (Tetraodon nigroviridis). To determine whether miRNAs participate in IFN-γ-related immune responses, T. nigroviridis spleen cells were treated with recombinant IFN-γ isoforms, and a Solexa high-throughput sequencing method was used to identify miRNAs. In total, 1,556, 1,538 and 1,573 miRNAs were found in the three samples, and differentially expressed miRNAs were determined. In total, 398 miRNAs were differentially expressed after rIFN-γ1 treatment, and 438 miRNAs were differentially expressed after rIFN-γ2 treatment; additionally, 403 miRNAs were differentially expressed between the treatment groups. Ten differentially expressed miRNAs were chosen for validation using qRT-PCR. Target genes for the differentially expressed miRNAs were predicted, and GO and KEGG analyses were performed. This study provides basic knowledge regarding fish IFN-γ-induced miRNAs and offers clues for further studies into the mechanisms underlying fish IFN-γ-mediated immune responses.
    Full-text · Article · May 2014 · PLoS ONE
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    • "We also identified the NAD-dependent deacetylase Sirtuin1 (SIRT1) as a direct target for miR-142-5p, one of the two functional mature forms of miR-142 [8]. MiR-142 has been extensively studied in the hematopoietic cell lineage, where it regulates differentiation of T lymphocytes and myeloid cells [13]–[16]. In addition to SIVE, miR-142 expression in neurons has been reported following nerve crush injury [17] and cocaine treatment [18]. "
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    ABSTRACT: Aberrant expression of microRNAs (miRs) has been implicated in the pathogenesis of several neurodegenerative disorders. In HIV-associated neurocognitive disorders (HAND), miR-142 was found to be upregulated in neurons and myeloid cells in the brain. We investigated the downstream effects of chronic miR-142 upregulation in neuronal cells by comparing gene expression in stable clones of the human neuroblastoma cell line BE(2)M17 expressing miR-142 to controls. Microarray analysis revealed that miR-142 expression led to a reduction in monoamine oxidase (MAO) A mRNA, which was validated by qRT-PCR. In addition to the mRNA, the MAOA protein level and enzyme activity were also reduced. Examination of primary human neurons revealed that miR-142 expression indeed resulted in a downregulation of MAOA protein level. Although MAOA is not a direct target of miR-142, SIRT1, a key transcriptional upregulator of MAOA is, thus miR-142 downregulation of MAOA expression is indirect. MiR-142 induced decrease in MAOA expression and activity may contribute to the changes in dopaminergic neurotransmission reported in HAND.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "High-level expression is maintained in adult bone-marrow-derived HSPCs (Flt3 À KLS) (Figure 1E), consistent with the prior observations that miR-142-3p is abundant specifically in hematopoietic cells (Bissels et al., 2011; Chen et al., 2004). miR-142-3p is absolutely conserved across vertebrates and has been previously reported to modulate the maturation of the myeloid, erythroid, and T cell lineages (Chen et al., 2004; Nishiyama et al., 2012; Wang et al., 2012b), but its role in the ontogeny of HSCs has not been investigated . miR-142-3p is likely to be the major functional form of this miRNA in HSC development as the opposite strand of miR-142, miR-142-5p, is virtually undetectable in endothelium and pre-HSCs and is expressed at a much lower level than miR-142-3p in embryonic HSPCs (almost 1,000-fold lower expression, Figure 1E). "
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    ABSTRACT: Hematopoietic stem cells (HSCs) emerge during embryogenesis from hemogenic endothelium, but it remains unclear how the HSC lineage is initially established from mesoderm during ontogeny. In Xenopus, the definitive hemangioblast precursors of the HSC lineage have been identified in dorsal lateral plate (DLP) mesoderm, and a transcriptional gene regulatory network (GRN) controlling hemangioblast programming has been elucidated. Herein, we identify an essential role for microRNAs (miRNAs) in establishing the mesodermal lineage leading to both HSC emergence and vasculogenesis and determine that a single miRNA, miR-142-3p, is primarily responsible for initiation of definitive hemangioblast specification. miR-142-3p forms a double-negative gate unlocking entry into the hemangioblast program, in part by inhibiting TGFβ signaling. Our results table miR-142-3p as a master regulator of HSC lineage specification, sitting at the apex of the hierarchy programming the adult hemangioblast, thus illustrating that miRNAs can act as instructive determinants of cell fate during development.
    Preview · Article · Jul 2013 · Developmental Cell
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