title: Sox18 genetically interacts with VegfC to regulate lymphangiogenesis in zebrafish.
abstract: 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.
  
  
  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.
authors.affiliation: Dipartimento di Scienze Biomolecolari e Biotecnologie, Universita' degli Studi di Milano, Milan, Italy.
authors.forename: Solei
authors.initials: S
authors.lastname: Cermenati
authors.forename: Silvia
authors.initials: S
authors.lastname: Moleri
authors.forename: Christine
authors.initials: C
authors.lastname: Neyt
authors.forename: Erica
authors.initials: E
authors.lastname: Bresciani
authors.forename: Silvia
authors.initials: S
authors.lastname: Carra
authors.forename: Daniela R
authors.initials: DR
authors.lastname: Grassini
authors.forename: Alice
authors.initials: A
authors.lastname: Omini
authors.forename: Michela
authors.initials: M
authors.lastname: Goi
authors.forename: Franco
authors.initials: F
authors.lastname: Cotelli
authors.forename: Mathias
authors.initials: M
authors.lastname: François
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Hogan
authors.forename: Monica
authors.initials: M
authors.lastname: Beltrame
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001808:Blood Vessels / Q000196:embryology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D042583:Lymphangiogenesis / Q000235:genetics*; D051379:Mice; D023421:Models, Animal; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D055760:SOXF Transcription Factors / Q000235:genetics* / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000235:genetics*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; D055760:SOXF Transcription Factors; C490653:Sox18 protein, mouse; D042582:Vascular Endothelial Growth Factor C
keywords: Sox transcription factors; lymphangiogenesis; lymphedema; vascular development; zebrafish