HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development.
Sébastien GauvritAlethia VillasenorBoris StrilicPhilip KitchenMichelle M CollinsRubén Marín-JuezStefan GuentherHans-Martin MaischeinNana FukudaMaurice A CanhamJoshua M BrickmanClifford W BoguePadma-Sheela JayaramanDidier Y R StainierPublished in: Nature communications (2018)
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.
Keyphrases
- transcription factor
- endothelial cells
- vascular endothelial growth factor
- acute myeloid leukemia
- tyrosine kinase
- lymph node
- poor prognosis
- high glucose
- dna binding
- genome wide
- binding protein
- genome wide identification
- gene expression
- copy number
- single molecule
- dna methylation
- long non coding rna
- regulatory t cells
- oxidative stress
- case control