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

Sébastien 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 and Didier Y. R. Stainier ()
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Sébastien Gauvrit: Max Planck Institute for Heart and Lung Research
Alethia Villasenor: Max Planck Institute for Heart and Lung Research
Boris Strilic: Max Planck Institute for Heart and Lung Research
Philip Kitchen: University of Birmingham
Michelle M. Collins: Max Planck Institute for Heart and Lung Research
Rubén Marín-Juez: Max Planck Institute for Heart and Lung Research
Stefan Guenther: Max Planck Institute for Heart and Lung Research
Hans-Martin Maischein: Max Planck Institute for Heart and Lung Research
Nana Fukuda: Max Planck Institute for Heart and Lung Research
Maurice A. Canham: MRC Centre for Regenerative Medicine
Joshua M. Brickman: University of Copenhagen
Clifford W. Bogue: Yale University School of Medicine
Padma-Sheela Jayaraman: University of Birmingham
Didier Y. R. Stainier: Max Planck Institute for Heart and Lung Research

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05039-1

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