1. Shear stimulation of FOXC1 and FOXC2 differentially regulates cytoskeletal activity during lymphatic valve maturation
- Author
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Amélie Sabine, Ting Liu, Pieter R. Norden, Ying Wang, Tatiana V. Petrova, Tsutomu Kume, and Cansaran Saygili Demir
- Subjects
0301 basic medicine ,Mouse ,Cell junction ,lymphatic valve ,Mice ,0302 clinical medicine ,Mechanotransduction ,Biology (General) ,Cytoskeleton ,Cells, Cultured ,Mice, Knockout ,biology ,Chemistry ,mesentery ,General Neuroscience ,Gene Expression Regulation, Developmental ,Forkhead Transcription Factors ,General Medicine ,Cell biology ,Lymphatic Endothelium ,Lymphatic system ,030220 oncology & carcinogenesis ,Animals ,Embryo, Mammalian ,Embryonic Development ,Endothelial Cells/metabolism ,Forkhead Transcription Factors/genetics ,Forkhead Transcription Factors/metabolism ,Humans ,Lymphatic System/growth & development ,Lymphatic System/metabolism ,cell biology ,developmental biology ,lymphatic endothelial cell ,mouse ,Medicine ,FOXC2 ,Research Article ,QH301-705.5 ,government.form_of_government ,Science ,General Biochemistry, Genetics and Molecular Biology ,Focal adhesion ,Adherens junction ,Lymphatic System ,03 medical and health sciences ,General Immunology and Microbiology ,Endothelial Cells ,Cell Biology ,eye diseases ,030104 developmental biology ,biology.protein ,government ,sense organs ,Developmental Biology - Abstract
Mutations in the transcription factor FOXC2 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 of Foxc2 induced valve degeneration, which is exacerbated in Foxc1; Foxc2 mutants. FOXC1 knockdown (KD) in human lymphatic endothelial cells increased focal adhesions and actin stress fibers whereas FOXC2-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 FOXC2 invitro and vivo respectively, but only ameliorated valve degeneration in Foxc2 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.
- Published
- 2020