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

Sebastian Gauvrit, Alethia Villasenor, Boris Strilic, Philip Kitchen, Michelle M. Collins, Rubén Marín-Juez, Stefan Guenther, Hans-Martin Maischein, Nana Fukuda, Maurice A. Canham, Joshua M. Brickman, Clifford W. Bogue, Padma-Sheela Jayaraman, Didier Y. R. Stainier

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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.
Original languageEnglish
Article number2704
Number of pages14
JournalNature Communications
Volume9
Issue number1
Early online date13 Jul 2018
DOIs
Publication statusPublished - Dec 2018

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