Mechanotransduction, PROX1, and FOXC2 Cooperate to Control Connexin37 and Calcineurin during Lymphatic-Valve Formation

Amélie Sabine, Yan Agalarov, Hélène Maby-ElHajjami, Muriel Jaquet, René Hägerling, Cathrin Pollmann, Damien Bebber, Anna Pfenniger, Naoyuki Miura, Olivier Dormond, Jean Marie Calmes, Ralf H. Adams, Taija Mäkinen, Friedemann Kiefer, Brenda R. Kwak, Tatiana V. Petrova*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

294 Scopus citations


Lymphatic valves are essential for efficient lymphatic transport, but the mechanisms of early lymphatic-valve morphogenesis and the role of biomechanical forces are not well understood. We found that the transcription factors PROX1 and FOXC2, highly expressed from the onset of valve formation, mediate segregation of lymphatic-valve-forming cells and cell mechanosensory responses to shear stress invitro. Mechanistically, PROX1, FOXC2, and flow coordinately control expression of the gap junction protein connexin37 and activation of calcineurin/NFAT signaling. Connexin37 and calcineurin are required for the assembly and delimitation of lymphatic valve territory during development and for its postnatal maintenance. We proposea model in which regionally increased levels/activation states of transcription factors cooperate with mechanotransduction to induce a discrete cell-signaling pattern and morphogenetic event, such as formation of lymphatic valves. Our results also provide molecular insights into the role of endothelial cell identity in the regulation of vascular mechanotransduction. Video Abstract: Blood flow is one of the regulators of vascular morphogenesis. By examining the contribution of biomechanical forces to lymphatic vascular development, Sabine etal. provide insight into how the interplay between mechanotransduction and the lymphatic endothelial transcription factors Prox1 and Foxc2 functions to regulate downstream signaling and induce lymphatic valve formation.

Original languageEnglish (US)
Pages (from-to)430-445
Number of pages16
JournalDevelopmental Cell
Issue number2
StatePublished - Feb 14 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Molecular Biology
  • Cell Biology
  • Developmental Biology


Dive into the research topics of 'Mechanotransduction, PROX1, and FOXC2 Cooperate to Control Connexin37 and Calcineurin during Lymphatic-Valve Formation'. Together they form a unique fingerprint.

Cite this