The receptor protein-tyrosine phosphatase, Dep1, acts in arterial/venous cell fate decisions in zebrafish development

Dept is a transmembrane protein-tyrosine phosphatase (PTP) that is expressed ill vascular endothelial cells and has turner suppresser activity. Mouse models with gene targeted Dep1 either show vascular defects, or do not show any defects at all. We used the zebrafish to investigate the role of Dept in early development. The zebrafish genome encodes two highly homologous Dept genes, Dep1a and Dep1b. Morpholinos specific for Dep1a and Dep1b induced defects in vasculature, resulting in defective blood circulation. However, Green Fluorescent Protein expression in flila::gp1 transgenic embryos and cdh5 expression, markers of vascular endothelial cells, were normal upon Dep1a- and Dep1b-MO injection. Molecular markers indicated that arterial specification was reduced and venous markers were expanded in Dep1 morphants. Moreover, the Dep1a/Dep1b knockdowns were rescued by inhibition of Phosphatidylinositol-3 kinase (PI3K) and by expression of active Notch and Grl/Hey2. Our results suggest a model in which Dept acts upstream in a signaling pathway inhibiting P13K, resulting in expression of Notch and Gr1, thus regulating arterial specification in development. (C) 2008 Elsevier Inc. All rigllts reserved.