TY - JOUR
T1 - miR-31 functions as a negative regulator of lymphatic vascular lineage-specific differentiation in vitro and vascular development in vivo
AU - Leslie Pedrioli, Deena M.
AU - Karpanen, Terhi
AU - Dabouras, Vasilios
AU - Jurisic, Giorgia
AU - Van De Hoek, Glenn
AU - Shin, Jay W.
AU - Marino, Daniela
AU - Kälin, Roland E.
AU - Leidel, Sebastian
AU - Cinelli, Paolo
AU - Schulte-Merker, Stefan
AU - Brändli, Andre W.
AU - Detmar, Michael
N1 - MEDLINE® is the source for the MeSH terms of this document.
PY - 2010/7
Y1 - 2010/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77954381998&partnerID=8YFLogxK
U2 - 10.1128/MCB.00185-10
DO - 10.1128/MCB.00185-10
M3 - Article
C2 - 20479124
AN - SCOPUS:77954381998
SN - 0270-7306
VL - 30
SP - 3620
EP - 3634
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 14
ER -