miR-31 functions as a negative regulator of lymphatic vascular lineage-specific differentiation in vitro and vascular development in vivo

Deena M. Leslie Pedrioli, Terhi Karpanen, Vasilios Dabouras, Giorgia Jurisic, Glenn Van De Hoek, Jay W. Shin, Daniela Marino, Roland E. Kälin, Sebastian Leidel, Paolo Cinelli, Stefan Schulte-Merker, Andre W. Brändli, Michael Detmar (Lead / Corresponding author)

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    74 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)3620-3634
    Number of pages15
    JournalMolecular and Cellular Biology
    Volume30
    Issue number14
    DOIs
    Publication statusPublished - Jul 2010

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    Leslie Pedrioli, D. M., Karpanen, T., Dabouras, V., Jurisic, G., Van De Hoek, G., Shin, J. W., Marino, D., Kälin, R. E., Leidel, S., Cinelli, P., Schulte-Merker, S., Brändli, A. W., & Detmar, M. (2010). miR-31 functions as a negative regulator of lymphatic vascular lineage-specific differentiation in vitro and vascular development in vivo. Molecular and Cellular Biology, 30(14), 3620-3634. https://doi.org/10.1128/MCB.00185-10