FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1.
The mechanisms of blood vessel maturation into distinct parts of the blood vasculature such as arteries, veins, and capillaries have been the subject of intense investigation over recent years. In contrast, our knowledge of lymphatic vessel maturation is still fragmentary. In this study, we provide a molecular and morphological characterization of the major steps in the maturation of the primary lymphatic capillary plexus into collecting lymphatic vessels during development and show that forkhead transcription factor Foxc2 controls this process. We further identify transcription factor NFATc1 as a novel regulator of lymphatic development and describe a previously unsuspected link between NFATc1 and Foxc2 in the regulation of lymphatic maturation. We also provide a genome-wide map of FOXC2-binding sites in lymphatic endothelial cells, identify a novel consensus FOXC2 sequence, and show that NFATc1 physically interacts with FOXC2-binding enhancers. As damage to collecting vessels is a major cause of lymphatic dysfunction in humans, our results suggest that FOXC2 and NFATc1 are potential targets for therapeutic intervention.
Norrmén
Camilla
C
Molecular Cancer Biology Program, Biomedicum Helsinki, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Ivanov
Konstantin I
KI
Cheng
Jianpin
J
Zangger
Nadine
N
Delorenzi
Mauro
M
Jaquet
Muriel
M
Miura
Naoyuki
N
Puolakkainen
Pauli
P
Horsley
Valerie
V
Hu
Junhao
J
Augustin
Hellmut G
HG
Ylä-Herttuala
Seppo
S
Alitalo
Kari
K
Petrova
Tatiana V
TV
D000818:Animals; D001485:Basement Membrane / Q000502:physiology; D001808:Blood Vessels / Q000502:physiology; D002196:Capillaries / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006351:Heart Valves / Q000502:physiology; D042601:Lymphatic Vessels / Q000473:pathology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000502:physiology*; D012879:Skin Physiological Phenomena
D051858:Forkhead Transcription Factors; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C082078:mesenchyme fork head 1 protein