miR-31 Functions as a Negative Regulator of Lymphatic Vascular Lineage-Specific Differentiation In Vitro and Vascular Development In Vivo

Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zürich, Wolfgang-Pauli-Str. 10, HCI H303, CH-8093 Zürich, Switzerland.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/2010; 30(14):3620-34. DOI: 10.1128/MCB.00185-10
Source: PubMed


The lymphatic vascular system maintains tissue fluid homeostasis, helps mediate afferent immune responses, and promotes cancer metastasis. To address the role microRNAs (miRNAs) play in the development and function of the lymphatic vascular system, we defined the in vitro miRNA expression profiles of primary human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BVECs) and identified four BVEC signature and two LEC signature miRNAs. Their vascular lineage-specific expression patterns were confirmed in vivo by quantitative real-time PCR and in situ hybridization. Functional characterization of the BVEC signature miRNA miR-31 identified a novel BVEC-specific posttranscriptional regulatory mechanism that inhibits the expression of lymphatic lineage-specific transcripts in vitro. We demonstrate that suppression of lymphatic differentiation is partially mediated via direct repression of PROX1, a transcription factor that functions as a master regulator of lymphatic lineage-specific differentiation. Finally, in vivo studies of Xenopus and zebrafish demonstrated that gain of miR-31 function impaired venous sprouting and lymphatic vascular development, thus highlighting the importance of miR-31 as a negative regulator of lymphatic development. Collectively, our findings identify miR-31 is a potent regulator of vascular lineage-specific differentiation and development in vertebrates.

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Available from: André W Brändli, May 05, 2014
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    • "Targeted functions of hsa-miR-31 include angiogenesis, where its upregulation increases blood, but not lymphatic vessels sprouting [48], and acute inflammation [49]. We found that hsa-miR-31 is mostly up-regulated in peritumoral inflammatory cells, compared to cancer and normal cells. "
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    • "We previously established the Xenopus laevis tadpole as a genetic model for lymphangiogenesis research, phenocopying deficiencies of known mammalian lymphatic genes (Ny et al., 2005). We and others further applied the tadpole model to investigate molecular regulation of lymphatic vascular development, including its use in chemical library screens to identify anti-lymph/angiogenesis compounds (Kälin et al., 2009; Marino et al., 2011; Ny et al., 2008; Leslie Pedrioli et al., 2010). In these studies, visualization of the blood-and lymphatic vasculature depended on staining by in situ hybridization (ISH). "
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    • "One of the CB-EPC-dominant microRNAs is miR-31, a pro-angiogenic miRNA that enhances endothelial cell migration [18,37]. MiR-31 has recently been documented as a signature BEC miRNA that negatively regulates lymphatic endothelial cell identity and lymphatic vascular development by targeting Prox1, a transcription factor that functions as a master regulator of lymphatic lineage-specific differentiation [45]. In the present study, we further showed that miR-31 is a dominant miRNA in CB-EPCs, and its overexpression is crucial for EPCs to possess superior angiogenic ability (Figure 4). "
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