The protein-tyrosine phosphatase Shp2 is essential for lymphatic endothelial cell differentiation in zebrafish

Mutations in genes associated with the VEGFC/VEGFR3 signaling pathway are strongly linked to a range of developmental and functional defects in the lymphatic system. PTPN11 encodes SHP2, a protein-tyrosine phosphatase that plays a critical role in receptor protein-tyrosine kinase (RTK) signaling. In this study, we investigated lymphangiogenesis in mutant zebrafish embryos lacking functional Shp2 and demonstrate that Shp2 is essential for normal lymphatic development in the trunk and head regions of zebrafish embryos. Embryos lacking functional Shp2 failed to develop lymphatic vessels and lymphatic endothelial cells (LECs), whereas venous intersegmental vessel (vISV) formation remained unaffected. While endothelial cells sprouted normally from the posterior cardinal vein (PCV), they did not migrate to the horizontal myoseptum to form parachordal lymphangioblast (PL) cells. Rescue experiments using Shp2 mutants demonstrated that catalytic activity and signaling properties of Shp2 are required for restoration of normal lymphangiogenesis. These findings highlight a pivotal role for Shp2 signaling in the migration and differentiation of lymphatic endothelial cells without affecting venous angiogenesis.