title: FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1.
abstract: 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.
authors.affiliation: Molecular Cancer Biology Program, Biomedicum Helsinki, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Camilla
authors.initials: C
authors.lastname: Norrmén
authors.forename: Konstantin I
authors.initials: KI
authors.lastname: Ivanov
authors.forename: Jianpin
authors.initials: J
authors.lastname: Cheng
authors.forename: Nadine
authors.initials: N
authors.lastname: Zangger
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Muriel
authors.initials: M
authors.lastname: Jaquet
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.forename: Pauli
authors.initials: P
authors.lastname: Puolakkainen
authors.forename: Valerie
authors.initials: V
authors.lastname: Horsley
authors.forename: Junhao
authors.initials: J
authors.lastname: Hu
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
mesh_terms: 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
chemical_list: D051858:Forkhead Transcription Factors; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C082078:mesenchyme fork head 1 protein