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      Zebrafish microRNA-126 determines hematopoietic cell fate through c-Myb

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          Abstract

          Precise regulatory mechanisms are required to appropriately modulate the cellular levels of transcription factors controlling cell fate decisions during blood cell development. Here, we show that miR-126 is a novel physiological regulator of the proto-oncogene c-myb during definitive hematopoiesis. We show that knockdown of miR-126 results in increased c-Myb levels and promotes erythropoiesis at the expense of thrombopoiesis in vivo. We further provide evidence that specification of thrombocyte versus erythrocyte cell lineages is altered by the concerted activities of the miRNAs miR-126 and miR-150. Both microRNAs are required but not sufficient individually to precisely regulate the cell fate decision between erythroid and megakaryocytic lineages during definitive hematopoiesis in vivo. These results support the notion that microRNAs not only act to provide precision to developmental programs but also are essential determinants in the control of variable potential functions of a single gene during hematopoiesis.

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          Most cited references 44

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          Prediction of mammalian microRNA targets.

          MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
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            miR-126 regulates angiogenic signaling and vascular integrity.

            Precise regulation of the formation, maintenance, and remodeling of the vasculature is required for normal development, tissue response to injury, and tumor progression. How specific microRNAs intersect with and modulate angiogenic signaling cascades is unknown. Here, we identified microRNAs that were enriched in endothelial cells derived from mouse embryonic stem (ES) cells and in developing mouse embryos. We found that miR-126 regulated the response of endothelial cells to VEGF. Additionally, knockdown of miR-126 in zebrafish resulted in loss of vascular integrity and hemorrhage during embryonic development. miR-126 functioned in part by directly repressing negative regulators of the VEGF pathway, including the Sprouty-related protein SPRED1 and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-beta). Increased expression of Spred1 or inhibition of VEGF signaling in zebrafish resulted in defects similar to miR-126 knockdown. These findings illustrate that a single miRNA can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.
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              MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb.

              MiR-150 is a microRNA (miRNA) specifically expressed in mature lymphocytes, but not their progenitors. A top predicted target of miR-150 is c-Myb, a transcription factor controlling multiple steps of lymphocyte development. Combining loss- and gain-of-function gene targeting approaches for miR-150 with conditional and partial ablation of c-Myb, we show that miR-150 indeed controls c-Myb expression in vivo in a dose-dependent manner over a narrow range of miRNA and c-Myb concentrations and that this dramatically affects lymphocyte development and response. Our results identify a key transcription factor as a critical target of a stage-specifically expressed miRNA in lymphocytes and suggest that this and perhaps other miRNAs have evolved to control the expression of just a few critical target proteins in particular cellular contexts.
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                Author and article information

                Journal
                8704895
                5536
                Leukemia
                Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
                0887-6924
                1476-5551
                2 November 2010
                16 November 2010
                March 2011
                1 September 2011
                : 25
                : 3
                : 506-514
                Affiliations
                [1 ] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
                [2 ] Institute of Cancer, Barts and the London School of Medicine, London, UK
                [3 ] Division of Cell and Molecular Biology, University Health Network, and Department of Molecular Genetics, University of Toronto, Toronto, ON
                [4 ] Division of Hematology/Oncology, Department of Pediatrics, Children’s Hospital, Harvard Medical School, Boston, MA 02114, USA
                Author notes
                [5 ]correspondence to Clemens Grabher; current address: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany; phone: +497247829158; fax: +49 7247823354; clemens.grabher@ 123456kit.edu
                [*]

                these authors contributed equally to this work

                Article
                nihpa246535
                10.1038/leu.2010.280
                3053419
                21079614

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                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA093152-01 ||CA
                Categories
                Article

                Oncology & Radiotherapy

                thrombocyte, mir-150, zebrafish, c-myb, mir-126, hematopoiesis

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