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

Autor: Amélie Sabine, Ting Liu, Pieter R. Norden, Ying Wang, Tatiana V. Petrova, Tsutomu Kume, Cansaran Saygili Demir
Jazyk: angličtina
Rok vydání: 2020
Předmět:
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
Zdroj: eLife, Vol 9 (2020)
eLife
eLife, vol. 9, pp. e53814
Popis: 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.
Databáze: OpenAIRE
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