PUBLICATION

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

Authors
Gauvrit, S., Villasenor, A., Strilic, B., Kitchen, P., Collins, M.M., Marín-Juez, R., Guenther, S., Maischein, H.M., Fukuda, N., Canham, M.A., Brickman, J.M., Bogue, C.W., Jayaraman, P.S., Stainier, D.Y.R.
ID
ZDB-PUB-180715-2
Date
2018
Source
Nature communications   9: 2704 (Journal)
Registered Authors
Maischein, Hans-Martin, Marín-Juez, Rubén, Stainier, Didier
Keywords
none
Datasets
GEO:GSE111963
MeSH Terms
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • Embryo, Mammalian
  • Lymphangiogenesis/genetics*
  • Mice
  • Homeodomain Proteins/genetics*
  • Homeodomain Proteins/metabolism
  • Tumor Suppressor Proteins/genetics*
  • Tumor Suppressor Proteins/metabolism
  • Vascular Endothelial Growth Factor C/genetics*
  • Vascular Endothelial Growth Factor C/metabolism
  • Cell Line
  • Embryo, Nonmammalian
  • Transcription, Genetic
  • Animals, Genetically Modified
  • Lymphatic Vessels/cytology
  • Lymphatic Vessels/metabolism
  • Signal Transduction
  • Animals
  • Repressor Proteins/deficiency
  • Repressor Proteins/genetics*
  • Gene Expression Regulation, Developmental*
  • Endothelial Cells/cytology
  • Endothelial Cells/metabolism
  • Blood Vessels/cytology
  • Blood Vessels/growth & development
  • Blood Vessels/metabolism
  • Neovascularization, Physiologic/genetics
  • Vascular Endothelial Growth Factor Receptor-3/genetics*
  • Vascular Endothelial Growth Factor Receptor-3/metabolism
  • Zebrafish
  • Base Sequence
  • Humans
(all 34)
PubMed
30006544 Full text @ Nat. Commun.
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.
Genes / Markers
Figures
Figure Gallery (10 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b16
    Deficiency
    bns136TgTransgenic Insertion
      ci1TgTransgenic Insertion
        is4TgTransgenic Insertion
          nim5TgTransgenic Insertion
            nz101TgTransgenic Insertion
              s721
                Insertion
                s722
                  Small Deletion
                  s843TgTransgenic Insertion
                    y7TgTransgenic Insertion
                      1 - 10 of 10
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      hhexTALEN1-hhexTALEN
                      1 - 1 of 1
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                      Fish
                      Antibodies
                      Name Type Antigen Genes Isotypes Host Organism
                      Ab7-prox1polyclonalRabbit
                      1 - 1 of 1
                      Show
                      Orthology
                      Gene Orthology
                      flt4
                      1 - 1 of 1
                      Show
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      DsRedEFGDsRed
                      EGFPEFGEGFP
                      KALTA4EFGKALTA4
                      mCherryEFGmCherry
                      TagRFPEFGTagRFP
                      TomatoEFGTomato
                      1 - 6 of 6
                      Show
                      Mapping
                      No data available