title: Novel zebrafish model reveals a critical role for MAPK in lymphangiogenesis.
abstract: OBJECTIVE
  Lymphatic disorders are poorly understood with few animal models. We designed a novel assay to measure lymphatic development using transgenic zebrafish with fluorescently labeled endothelial cells. Two major branches of the vascular endothelial growth factor receptor (VEGFR) signaling pathway were examined: the MAPK and PI3K pathways.
  
  
  METHODS
  Direct visualization of lymphatic development was performed in control embryos or under chemical inhibition. Treatment involved a 6-hour pulse of inhibitor at 3 days postfertilization. Fish were analyzed for the presence of the thoracic duct (TD) at 4 days postfertilization (n > 100 specimens).
  
  
  RESULTS
  Thoracic duct formation was prevented using selective inhibitors against kinases (MAPK, PI3K/TOR, or VEGFR). These kinases were important for TD formation because the lymphatic vessel failed to form in most of treated animals. Remarkably, MAPK pathway inhibition most robustly reduced lymphangiogenesis, demonstrated by a lack of lymphatic endothelial cells.
  
  
  CONCLUSIONS
  We conclude that MAPK pathway function downstream of the VEGFRs is crucial at the early stages of TD development. This study provides a novel animal model and a potential target pathway for further investigation. We suggest further examination of MAPK pathway deregulation as a potential mechanism underlying lymphatic disease in humans.
authors.affiliation: Vascular Biology Program, Vascular Anomalies Center and Department of Surgery Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: R Dawn
authors.initials: RD
authors.lastname: Fevurly
authors.forename: Sean
authors.initials: S
authors.lastname: Hasso
authors.forename: Alexander
authors.initials: A
authors.lastname: Fye
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fishman
authors.forename: Joanne
authors.initials: J
authors.lastname: Chan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042583:Lymphangiogenesis / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D015027:Zebrafish
chemical_list: D040262:Receptors, Vascular Endothelial Growth Factor