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The Weinstein Laboratory

Molecular Dissection of Arterial-Venous Development

We have uncovered a molecular pathway regulating the acquisition of arterial-venous identity consisting of sonic hedgehog (SHH), vascular endothelial growth factor (VEGF), and notch signaling acting in series. Subsequent studies from other labs have supported a similar role for this novel pathway during mammalian arterial differentiation. Using genetic screening and positional/candidate cloning methods we identified ‘plcg1-y10, a mutant in phospholipase C gamma-1 with angiogenesis and arterial differentiation defects, and used this to demonstrate that this gene is a major downstream effector of VEGF signaling in vivo. We are continuing efforts to dissect arterial-venous development using genetic screens, microarrays, and novel transgenic tools. Our ongoing screens have identified new loci that are required for proper arterial or venous vascular development, and cloning and molecular characterization of these new mutants is in progress. We have established microarray technology in the laboratory, and are screening animals with gain- or loss- of function in different steps of the previously characterized arterial differentiation pathway. Finally, we are establishing arterial- and venous-specific transgenic lines that will allow us to easily assay for arterial and venous differentiation states in vivo. See selected references.