Sox18 Genetically Interacts With VegfC to Regulate Lymphangiogenesis in Zebrafish

Cermenati, S., Moleri, S., Neyt, C., Bresciani, E., Carra, S., Grassini, D.R., Omini, A., Goi, M., Cotelli, F., François, M., Hogan, B.M., and Beltrame, M.
Arterioscler. Thromb. Vasc. Biol.   33(6): 1238-47 (Journal)
Registered Authors
Beltrame, Monica, Bresciani, Erica, Cotelli, Franco, Hogan, Ben M., Neyt, Christine
lymphangiogenesis, lymphedema, sox transcription factors, vascular development, zebrafish
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Blood Vessels/embryology
  • DNA-Binding Proteins/genetics
  • DNA-Binding Proteins/metabolism
  • Gene Expression Regulation, Developmental*
  • Lymphangiogenesis/genetics*
  • Mice
  • Models, Animal
  • Protein Interaction Domains and Motifs/genetics
  • SOXF Transcription Factors/genetics*
  • SOXF Transcription Factors/metabolism
  • Sensitivity and Specificity
  • Signal Transduction/genetics*
  • Vascular Endothelial Growth Factor C/genetics*
  • Vascular Endothelial Growth Factor C/metabolism
  • Zebrafish
23520166 Full text @ Arterioscler. Thromb. Vasc. Biol.

Objective—Lymphangiogenesis is regulated by transcription factors and by growth factor pathways, but their interplay has not been extensively studied so far. We addressed this issue in zebrafish.

Approach and Results—Mutations in the transcription factor–coding gene SOX18 and in VEGFR3 cause lymphedema, and the VEGFR3/Flt4 ligand VEGFC plays an evolutionarily conserved role in lymphangiogenesis. Here, we report a strong genetic interaction between Sox18 and VegfC in the early phases of lymphatic development in zebrafish. Knockdown of sox18 selectively impaired lymphatic sprouting from the cardinal vein and resulted in defective lymphatic thoracic duct formation. Sox18 and the related protein Sox7 play redundant roles in arteriovenous differentiation. We used a novel transgenic line that enables inducible expression of a dominant-negative mutant form of mouse Sox18 protein. Our data led us to conclude that Sox18 is crucially involved in lymphangiogenesis after arteriovenous differentiation. Combined partial knockdown of sox18 and vegfc, using subcritical doses of specific morpholinos, revealed a synergistic interaction in both venous and lymphatic sprouting from the cardinal vein and greatly impaired thoracic duct formation.

Conclusions—This interaction suggests a previously unappreciated crosstalk between the growth factor and transcription factor pathways that regulate lymphangiogenesis in development and disease.

Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes