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Nat Commun. 2018 Jul 13;9(1):2704. doi: 10.1038/s41467-018-05039-1.

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

Author information

1
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany. sebastien.gauvrit@mpi-bn.mpg.de.
2
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
3
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
4
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
5
ECCPS Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
6
School of Biological Sciences, Institute for Stem Cell Research, MRC Centre for Regenerative Medicine, Edinburgh, EH16 4UU, UK.
7
Novo Nordisk Foundation Centre for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, DK-2200, Denmark.
8
Department of Pediatrics, Yale University School of Medicine, New Haven, 06510, CT, USA.
9
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany. didier.stainier@mpi-bn.mpg.de.

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.

PMID:
30006544
PMCID:
PMC6045644
DOI:
10.1038/s41467-018-05039-1
[Indexed for MEDLINE]
Free PMC Article

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