Journal Article

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

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

2018

Overview

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. VEGFC, its receptor FLT4, and transcriptional effector PROX1 control formation of the lymphatic system but how is unclear. Here, the authors show that the transcription factor hematopoietically expressed homeobox (HHEX) regulates VEGFC, FLT4 and PROX1 in fish and mammals during angiogenic sprouting and lymphatic formation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 14/19 / 38 / 45/91 / 631/136/290 / 631/208/135 / 631/80/86/2368 / 64 / 64/116 / 64/60 / 96/31 / Amino acids / Angiogenesis / Animals / Animals, Genetically Modified / Base Sequence / Blood / Blood Vessels - cytology / Blood Vessels - growth & development / Blood Vessels - metabolism / Cell Line / Edema / Embryo, Mammalian / Embryo, Nonmammalian / Endothelial cells / Endothelial Cells - cytology / Endothelial Cells - metabolism / Gene expression / Gene Expression Regulation, Developmental / Heart / Homeobox / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humanities and Social Sciences / Humans / Lymphangiogenesis - genetics / Lymphatic system / Lymphatic Vessels - cytology / Lymphatic Vessels - metabolism / Mammals / Mice / Molecular chains / multidisciplinary / Neovascularization, Physiologic - genetics / Prospero-Related Homeobox 1 Protein / Regulators / Repressor Proteins - deficiency / Repressor Proteins - genetics / Science / Science (multidisciplinary) / Signal Transduction / Signaling / Stem cells / Transcription factors / Transcription, Genetic / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism / Vascular endothelial growth factor / Vascular endothelial growth factor C / Vascular Endothelial Growth Factor C - genetics / Vascular Endothelial Growth Factor C - metabolism / Vascular Endothelial Growth Factor Receptor-3 - genetics / Vascular Endothelial Growth Factor Receptor-3 - metabolism / Veins & arteries / Vertebrates / Zebrafish / Zebrafish Proteins - deficiency / Zebrafish Proteins - genetics / Zebrafish Proteins - metabolism