Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation.
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 in vitro. 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 propose a 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.
Division of Experimental Oncology, Multidisciplinary Oncology Center, University Hospital of Lausanne, Switzerland.
Amélie
A
Sabine
Yan
Y
Agalarov
Hélène
H
Maby-El Hajjami
Muriel
M
Jaquet
René
R
Hägerling
Cathrin
C
Pollmann
Damien
D
Bebber
Anna
A
Pfenniger
Naoyuki
N
Miura
Olivier
O
Dormond
Jean-Marie
JM
Calmes
Ralf H
RH
Adams
Taija
T
Mäkinen
Friedemann
F
Kiefer
Brenda R
BR
Kwak
Tatiana V
TV
Petrova
D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000502:physiology*; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000166:cytology* / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000097006:Gap Junction alpha-4 Protein; D000098551:Prospero-Related Homeobox 1 Protein
D019703:Calcineurin; D017630:Connexins; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D000097006:Gap Junction alpha-4 Protein; D000098551:Prospero-Related Homeobox 1 Protein; C082078:mesenchyme fork head 1 protein