PMID- 32510325
OWN - NLM
STAT- MEDLINE
DCOM- 20210312
LR  - 20210312
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 9
DP  - 2020 Jun 8
TI  - Shear stimulation of FOXC1 and FOXC2 differentially regulates cytoskeletal 
      activity during lymphatic valve maturation.
LID - 10.7554/eLife.53814 [doi]
LID - e53814
AB  - 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.
CI  - (c) 2020, Norden et al.
FAU - Norden, Pieter R
AU  - Norden PR
AUID- ORCID: 0000-0002-5960-5245
AD  - Feinberg Cardiovascular and Renal Research Institute, Department of Medicine, 
      Feinberg School of Medicine, Northwestern University, Chicago, United States.
FAU - Sabine, Amelie
AU  - Sabine A
AUID- ORCID: 0000-0002-7512-6703
AD  - Department of Oncology, Centre Hospitalier Universitaire Vaudois and University 
      of Lausanne, Epalinges, Switzerland.
FAU - Wang, Ying
AU  - Wang Y
AUID- ORCID: 0000-0002-7852-386X
AD  - Department of Biochemistry and Molecular Biology, College of Medicine and 
      Science, Mayo Clinic, Jacksonville, United States.
FAU - Demir, Cansaran Saygili
AU  - Demir CS
AD  - Department of Oncology, Centre Hospitalier Universitaire Vaudois and University 
      of Lausanne, Epalinges, Switzerland.
FAU - Liu, Ting
AU  - Liu T
AD  - Feinberg Cardiovascular and Renal Research Institute, Department of Medicine, 
      Feinberg School of Medicine, Northwestern University, Chicago, United States.
FAU - Petrova, Tatiana V
AU  - Petrova TV
AD  - Department of Oncology, Centre Hospitalier Universitaire Vaudois and University 
      of Lausanne, Epalinges, Switzerland.
FAU - Kume, Tsutomu
AU  - Kume T
AUID- ORCID: 0000-0002-6005-5316
AD  - Feinberg Cardiovascular and Renal Research Institute, Department of Medicine, 
      Feinberg School of Medicine, Northwestern University, Chicago, United States.
LA  - eng
GR  - R01 HL144129/HL/NHLBI NIH HHS/United States
GR  - R01 HL126920/HL/NHLBI NIH HHS/United States
GR  - P30 CA060553/CA/NCI NIH HHS/United States
GR  - T32 HL094293/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20200608
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (FOXC1 protein, human)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxc1 protein, mouse)
RN  - 0 (mesenchyme fork head 1 protein)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Embryo, Mammalian
MH  - Embryonic Development
MH  - Endothelial Cells/*metabolism
MH  - Forkhead Transcription Factors/genetics/*metabolism
MH  - Gene Expression Regulation, Developmental
MH  - Humans
MH  - Lymphatic System/growth & development/metabolism
MH  - Mice
MH  - Mice, Knockout
PMC - PMC7302880
OTO - NOTNLM
OT  - cell biology
OT  - developmental biology
OT  - lymphatic endothelial cell
OT  - lymphatic valve
OT  - mesentery
OT  - mouse
COIS- PN, AS, YW, CD, TL, TP, TK No competing interests declared
EDAT- 2020/06/09 06:00
MHDA- 2021/03/13 06:00
PMCR- 2020/06/08
CRDT- 2020/06/09 06:00
PHST- 2019/11/21 00:00 [received]
PHST- 2020/06/06 00:00 [accepted]
PHST- 2020/06/09 06:00 [pubmed]
PHST- 2021/03/13 06:00 [medline]
PHST- 2020/06/09 06:00 [entrez]
PHST- 2020/06/08 00:00 [pmc-release]
AID - 53814 [pii]
AID - 10.7554/eLife.53814 [doi]
PST - epublish
SO  - Elife. 2020 Jun 8;9:e53814. doi: 10.7554/eLife.53814.