HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development.

S Gauvrit, A Villasenor, B Strilic, P Kitchen, MM Collins, R Marín-Juez, S Guenther, HM Maischein, N Fukuda, MA Canham, JM Brickman, CW Bogue, DYR Stainier

Research output: Contribution to journalArticle

Abstract

Formation of the lymphatic system requires the coordinated expression of several key regulators: vascular endothelial growth factor C (VEGFC), its receptor FLT4, and a key transcriptional effector, PROX1. Yet, how expression of these signaling components is regulated remains poorly understood. Here, using a combination of genetic and molecular approaches, we identify the transcription factor hematopoietically expressed homeobox (HHEX) as an upstream regulator of VEGFC, FLT4, and PROX1 during angiogenic sprouting and lymphatic formation in vertebrates. By analyzing zebrafish mutants, we found that hhex is necessary for sprouting angiogenesis from the posterior cardinal vein, a process required for lymphangiogenesis. Furthermore, studies of mammalian HHEX using tissue-specific genetic deletions in mouse and knockdowns in cultured human endothelial cells reveal its highly conserved function during vascular and lymphatic development. Our findings that HHEX is essential for the regulation of the VEGFC/FLT4/PROX1 axis provide insights into the molecular regulation of lymphangiogenesis.
Original languageEnglish
Article number2704
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 13 Jul 2018

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Vascular Endothelial Growth Factor C
Homeobox Genes
regulators
Lymphangiogenesis
Blood Vessels
Lymphatic System
Endothelial cells
Zebrafish
effectors
angiogenesis
deletion
vertebrates
Vertebrates
lymphatic system
Molecular Biology
Veins
Transcription Factors
Endothelial Cells
veins
Tissue

Bibliographical note

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Cite this

Gauvrit, S ; Villasenor, A ; Strilic, B ; Kitchen, P ; Collins, MM ; Marín-Juez, R ; Guenther, S ; Maischein, HM ; Fukuda, N ; Canham, MA ; Brickman, JM ; Bogue, CW ; Stainier, DYR. / HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development. In: Nature Communications. 2018 ; Vol. 9.
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abstract = "Formation of the lymphatic system requires the coordinated expression of several key regulators: vascular endothelial growth factor C (VEGFC), its receptor FLT4, and a key transcriptional effector, PROX1. Yet, how expression of these signaling components is regulated remains poorly understood. Here, using a combination of genetic and molecular approaches, we identify the transcription factor hematopoietically expressed homeobox (HHEX) as an upstream regulator of VEGFC, FLT4, and PROX1 during angiogenic sprouting and lymphatic formation in vertebrates. By analyzing zebrafish mutants, we found that hhex is necessary for sprouting angiogenesis from the posterior cardinal vein, a process required for lymphangiogenesis. Furthermore, studies of mammalian HHEX using tissue-specific genetic deletions in mouse and knockdowns in cultured human endothelial cells reveal its highly conserved function during vascular and lymphatic development. Our findings that HHEX is essential for the regulation of the VEGFC/FLT4/PROX1 axis provide insights into the molecular regulation of lymphangiogenesis.",
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Gauvrit, S, Villasenor, A, Strilic, B, Kitchen, P, Collins, MM, Marín-Juez, R, Guenther, S, Maischein, HM, Fukuda, N, Canham, MA, Brickman, JM, Bogue, CW & Stainier, DYR 2018, 'HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development.', Nature Communications, vol. 9, 2704. https://doi.org/10.1038/s41467-018-05039-1

HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development. / Gauvrit, S; Villasenor, A; Strilic, B; Kitchen, P; Collins, MM; Marín-Juez, R; Guenther, S; Maischein, HM; Fukuda, N; Canham, MA; Brickman, JM; Bogue, CW; Stainier, DYR.

In: Nature Communications, Vol. 9, 2704, 13.07.2018.

Research output: Contribution to journalArticle

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AU - Gauvrit, S

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AU - Strilic, B

AU - Kitchen, P

AU - Collins, MM

AU - Marín-Juez, R

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AU - Maischein, HM

AU - Fukuda, N

AU - Canham, MA

AU - Brickman, JM

AU - Bogue, CW

AU - Stainier, DYR

N1 - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

PY - 2018/7/13

Y1 - 2018/7/13

N2 - Formation of the lymphatic system requires the coordinated expression of several key regulators: vascular endothelial growth factor C (VEGFC), its receptor FLT4, and a key transcriptional effector, PROX1. Yet, how expression of these signaling components is regulated remains poorly understood. Here, using a combination of genetic and molecular approaches, we identify the transcription factor hematopoietically expressed homeobox (HHEX) as an upstream regulator of VEGFC, FLT4, and PROX1 during angiogenic sprouting and lymphatic formation in vertebrates. By analyzing zebrafish mutants, we found that hhex is necessary for sprouting angiogenesis from the posterior cardinal vein, a process required for lymphangiogenesis. Furthermore, studies of mammalian HHEX using tissue-specific genetic deletions in mouse and knockdowns in cultured human endothelial cells reveal its highly conserved function during vascular and lymphatic development. Our findings that HHEX is essential for the regulation of the VEGFC/FLT4/PROX1 axis provide insights into the molecular regulation of lymphangiogenesis.

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