title: Tbx1 regulates Vegfr3 and is required for lymphatic vessel development.
abstract: Lymphatic dysfunction causes several human diseases, and tumor lymphangiogenesis is implicated in cancer spreading. TBX1 is the major gene for DiGeorge syndrome, which is associated with multiple congenital anomalies. Mutation of Tbx1 in mice recapitulates the human disease phenotype. In this study, we use molecular, cellular, and genetic approaches to show, unexpectedly, that Tbx1 plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3, a gene that is essential for lymphangiogenesis. Tbx1 activates Vegfr3 transcription in endothelial cells (ECs) by binding to an enhancer element in the Vegfr3 gene. Conditional deletion of Tbx1 in ECs causes widespread lymphangiogenesis defects in mouse embryos and perinatal death. Using the mesentery as a model tissue, we show that Tbx1 is not required for lymphatic EC differentiation; rather, it is required for the growth and maintenance of lymphatic vessels. Our findings reveal a novel pathway for the development of the lymphatic vessel network.
authors.affiliation: Program of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Annalisa
authors.initials: A
authors.lastname: Mupo
authors.forename: Tuong
authors.initials: T
authors.lastname: Huynh
authors.forename: Sara
authors.initials: S
authors.lastname: Cioffi
authors.forename: Matthew
authors.initials: M
authors.lastname: Woods
authors.forename: Chengliu
authors.initials: C
authors.lastname: Jin
authors.forename: Wallace
authors.initials: W
authors.lastname: McKeehan
authors.forename: LuAnn
authors.initials: L
authors.lastname: Thompson-Snipes
authors.forename: Antonio
authors.initials: A
authors.lastname: Baldini
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Illingworth
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics*; D042601:Lymphatic Vessels / Q000196:embryology*; D051379:Mice; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D042461:Vascular Endothelial Growth Factor A