miR-142 orchestrates a network of actin cytoskeleton regulators during megakaryopoiesis

Abstract

Genome-encoded microRNAs (miRNAs) provide a posttranscriptional regulatory layer that controls the differentiation and function of various cellular systems, including hematopoietic cells. miR-142 is one of the most prevalently expressed miRNAs within the hematopoietic lineage. To address the in vivo functions of miR-142, we utilized a novel reporter and a loss-of-function mouse allele that we have recently generated. In this study, we show that miR-142 is broadly expressed in the adult hematopoietic system. Our data further reveal that miR-142 is critical for megakaryopoiesis. Genetic ablation of miR-142 caused impaired megakaryocyte maturation, inhibition of polyploidization, abnormal proplatelet formation, and thrombocytopenia. Finally, we characterized a network of miR-142-3p targets which collectively control actin filament homeostasis, thereby ensuring proper execution of actin-dependent proplatelet formation. Our study reveals a pivotal role for miR-142 activity in megakaryocyte maturation and function, and demonstrates a critical contribution of a single miRNA in orchestrating cytoskeletal dynamics and normal hemostasis.DOI: http://dx.doi.org/10.7554/eLife.01964.001

Oncogenic microRNA-142-3p is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma

“…By targeting the oncogenes cluster of differentiation 133, ATP-binding cassette, subfamily G, member 3 and leucine-rich repeat-containing G protein-coupled receptor 5, miR-142-3p functions as a tumor suppressor in colon cancer cells (38). Other than its roles in tumorigenesis, miR-142 is also important for megakaryopoiesis, with the genetic ablation of miR-142 responsible for impaired megakaryocyte maturation, the inhibition of polyploidization, abnormal proplatelet formation and thrombocytopenia, through the orchestration of an actin cytoskeleton network (39).…”

MiR-142 Is Required for Staphylococcus aureus Clearance at Skin Wound Sites via Small GTPase-Mediated Regulation of the Neutrophil Actin Cytoskeleton

“…Our miR-142 −/− mice had a phenotype similar to that of another miR-142 −/− mouse strain, and exhibited splenomegaly, altered lymphocyte and red blood cell counts, and altered ratios of immune cells in the spleen (Supplementary Figure S3 and Supplementary Table S1) (Chapnik et al, 2014, Kramer et al, 2015. aureus at the wound sites and found that 6.2-fold more bacteria were present in the wounds of miR-142 −/− mice (3.6 × 10 6 CFU/ml) compared with those of WT mice (5.8 × 10 5 CFU/ml) at 3 days after injury (Figure 1h), suggesting that neutrophilic clearance of infection might be the mechanistic link to poor wound closure.…”

“…Chapnik and colleagues reported that megakaryocytes from miR-142 −/− mice exhibit disturbed actin cytoskeletal dynamics owing to changes in the expression levels of several cytoskeletal regulatory genes, such as cofilin-2 (Cfl2), Rho GTPase activating protein 35 (Arhgap35), and Wiskott-Aldrich syndrome-like (Wasl), all of which are target genes for miR-142-3p (Chapnik et al, 2014). Taken together with our results, this suggests that the miR-142 family might play a role in regulating neutrophil migration by modulating Rac and Rho expression levels and the consequent regulation of the actin cytoskeleton, which is clearly pivotal for efficient neutrophil migration.…”

Divergent target recognition by coexpressed 5′-isomiRs of miR-142-3p and selective viral mimicry

“…The inactivation of miR-142-3p causes defects in hematopoiesis in zebrafish (Nishiyama et al 2012) and prevents the specification of definitive hemangioblasts in Xenopus (Nimmo et al 2013). In mice, ablation of the miR-142 locus results in reduced numbers of CD4 + dendritic cells (Mildner et al 2013) and a severe impairment of platelet formation (Chapnik et al 2014). This latter phenotype is a consequence of the dysregulation of the actin cytoskeleton in megakaryocytes, the cell type responsible for platelet production (Chapnik et al 2014).…”

“…In mice, ablation of the miR-142 locus results in reduced numbers of CD4 + dendritic cells (Mildner et al 2013) and a severe impairment of platelet formation (Chapnik et al 2014). This latter phenotype is a consequence of the dysregulation of the actin cytoskeleton in megakaryocytes, the cell type responsible for platelet production (Chapnik et al 2014). miR-142-3p is coexpressed with an abundant 5 ′ -isomiR that lacks the 5 ′ -terminal U (Fig.…”