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

Pedrioli, D.M.L., 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., and Detmar, M.
Molecular and cellular biology   30(14): 3620-3634 (Journal)
Registered Authors
Karpanen, Terhi, Schulte-Merker, Stefan
miRNA post-transcriptional regulation, vascular development, lymphangiogenesis, PROX1, miR-31
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Base Sequence
  • Blood Vessels/cytology
  • Blood Vessels/growth & development
  • Blood Vessels/metabolism
  • Cell Differentiation/genetics
  • Cell Differentiation/physiology
  • Cells, Cultured
  • Endothelial Cells/cytology*
  • Endothelial Cells/metabolism*
  • Female
  • Gene Expression Profiling
  • Homeodomain Proteins/genetics
  • Homeodomain Proteins/metabolism
  • Humans
  • In Situ Hybridization
  • In Vitro Techniques
  • Lymphatic System/cytology*
  • Lymphatic System/growth & development*
  • Lymphatic System/metabolism
  • Mice
  • MicroRNAs/genetics*
  • MicroRNAs/metabolism
  • Polymerase Chain Reaction
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Tumor Suppressor Proteins/genetics
  • Tumor Suppressor Proteins/metabolism
  • Xenopus laevis/embryology
  • Xenopus laevis/genetics
  • Xenopus laevis/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
20479124 Full text @ Mol. Cell. Biol.
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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes