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


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.

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 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 4 BVEC-signature and 2 LEC-signature miRNAs. Their vascular lineage-specific expression patterns were confirmed in vivo by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). Functional characterization of the BVEC-signature miRNA, miR-31, identified a novel BVEC-specific post-transcriptional regulatory mechanism that inhibits the expression of lymphatic-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 in 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.

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 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 4 BVEC-signature and 2 LEC-signature miRNAs. Their vascular lineage-specific expression patterns were confirmed in vivo by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). Functional characterization of the BVEC-signature miRNA, miR-31, identified a novel BVEC-specific post-transcriptional regulatory mechanism that inhibits the expression of lymphatic-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 in 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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Laboratory Animal Science
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:July 2010
Deposited On:05 Jul 2010 15:59
Last Modified:05 Apr 2016 14:09
Publisher:American Society for Microbiology
ISSN:0270-7306
Publisher DOI:10.1128/MCB.00185-10
PubMed ID:20479124
Permanent URL: http://doi.org/10.5167/uzh-34495

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