title: The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors.
abstract: The mammalian lymphatic vasculature is important for returning fluids from the extracellular tissue milieu back to the blood circulation. We showed previously that Prox1 dosage is important for the development of the mammalian lymphatic vasculature. The lack of Prox1 activity results in the complete absence of lymphatic endothelial cells (LECs). In Prox1 heterozygous embryos, the number of LECs is reduced because of a decrease in the progenitor pool in the cardinal vein. This reduction is caused by some progenitor cells being unable to maintain Prox1 expression. In this study, we identified Vegfr3, the cognate receptor of the lymphangiogenic growth factor Vegfc, as a dosage-dependent, direct in vivo target of Prox1. Using various mouse models, we also determined that Vegfr3 regulates Prox1 by establishing a feedback loop necessary to maintain the identity of LEC progenitors and that Vegfc-mediated activation of Vegfr3 signaling is necessary to maintain Prox1 expression in LEC progenitors. We propose that this feedback loop is the main sensing mechanism controlling the number of LEC progenitors and, as a consequence, the number of budding LECs that will form the embryonic lymphatic vasculature.
authors.affiliation: Department of Genetics.
authors.forename: R Sathish
authors.initials: RS
authors.lastname: Srinivasan
authors.affiliation: Department of Genetics.
authors.forename: Noelia
authors.initials: N
authors.lastname: Escobedo
authors.affiliation: Department of Genetics.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Genetics.
authors.forename: Ashley
authors.initials: A
authors.lastname: Interiano
authors.affiliation: Department of Genetics.
authors.forename: Miriam E
authors.initials: ME
authors.lastname: Dillard
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
authors.forename: Suraj
authors.initials: S
authors.lastname: Mukatira
authors.affiliation: Department of Genetics.
authors.forename: Hyea Jin
authors.initials: HJ
authors.lastname: Gil
authors.affiliation: Wihuri Research Institute, Translational Cancer Biology Program, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Nurmi
authors.affiliation: Wihuri Research Institute, Translational Cancer Biology Program, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: Department of Genetics, guillermo.oliver@stjude.org.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Oliver
mesh_terms: D000818:Animals; D002452:Cell Count; D004625:Embryo, Nonmammalian; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology*; D066026:Endothelial Progenitor Cells / Q000166:cytology* / Q000502:physiology*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D042601:Lymphatic Vessels / Q000166:cytology / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: Prox1; Vegfr3; endothelial cell; lymphatics; mouse; progenitor