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The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors

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...

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Autores principales: Srinivasan, R. Sathish, Escobedo, Noelia, Yang, Ying, Interiano, Ashley, Dillard, Miriam E., Finkelstein, David, Mukatira, Suraj, Gil, Hyea Jin, Nurmi, Harri, Alitalo, Kari, Oliver, Guillermo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180978/
https://www.ncbi.nlm.nih.gov/pubmed/25274728
http://dx.doi.org/10.1101/gad.216226.113
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author Srinivasan, R. Sathish
Escobedo, Noelia
Yang, Ying
Interiano, Ashley
Dillard, Miriam E.
Finkelstein, David
Mukatira, Suraj
Gil, Hyea Jin
Nurmi, Harri
Alitalo, Kari
Oliver, Guillermo
author_facet Srinivasan, R. Sathish
Escobedo, Noelia
Yang, Ying
Interiano, Ashley
Dillard, Miriam E.
Finkelstein, David
Mukatira, Suraj
Gil, Hyea Jin
Nurmi, Harri
Alitalo, Kari
Oliver, Guillermo
author_sort Srinivasan, R. Sathish
collection PubMed
description 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.
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spelling pubmed-41809782015-04-01 The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors Srinivasan, R. Sathish Escobedo, Noelia Yang, Ying Interiano, Ashley Dillard, Miriam E. Finkelstein, David Mukatira, Suraj Gil, Hyea Jin Nurmi, Harri Alitalo, Kari Oliver, Guillermo Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2014-10-01 /pmc/articles/PMC4180978/ /pubmed/25274728 http://dx.doi.org/10.1101/gad.216226.113 Text en © 2014 Srinivasan et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Srinivasan, R. Sathish
Escobedo, Noelia
Yang, Ying
Interiano, Ashley
Dillard, Miriam E.
Finkelstein, David
Mukatira, Suraj
Gil, Hyea Jin
Nurmi, Harri
Alitalo, Kari
Oliver, Guillermo
The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors
title The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors
title_full The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors
title_fullStr The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors
title_full_unstemmed The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors
title_short The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors
title_sort prox1–vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180978/
https://www.ncbi.nlm.nih.gov/pubmed/25274728
http://dx.doi.org/10.1101/gad.216226.113
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