Shear stimulation of FOXC1 and FOXC2 differentially regulates cytoskeletal activity during lymphatic valve maturation

Mutations in the transcription factorFOXC2 are predominately associated with lymphedema. Herein, we demonstrate a key role for related factor FOXC1, in addition to FOXC2, in regulating cytoskeletal activity in lymphatic valves. FOXC1 is induced by laminar, but not oscillatory, shear and inducible, endothelial-specific deletion impaired postnatal lymphatic valve maturation in mice. However, deletion ofFoxc2 induced valve degeneration, which is exacerbated inFoxc1; Foxc2 mutants.FOXC1knockdown (KD) in human lymphatic endothelial cells increased focal adhesions and actin stress fibers whereasFOXC2-KD increased focal adherens and disrupted cell junctions, mediated by increased ROCK activation. ROCK inhibition rescued cytoskeletal or junctional integrity changes induced by inactivation of FOXC1 and FOXC2in vitro andvivo respectively, but only ameliorated valve degeneration inFoxc2 mutants. These results identify both FOXC1 and FOXC2 as mediators of mechanotransduction in the postnatal lymphatic vasculature and posit cytoskeletal signaling as a therapeutic target in lymphatic pathologies.
Source: eLife - Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research