Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets

Kalén, Mattias
Wallgard, Elisabet
Essner, Jeffrey
Asker, Noomi
Nasevicius, Aidas
Athley, Elisabet
Billgren, Erik
Larson, Jon
Wadman, Shannon
Norseng, Elizabeth
Clark, Karl
He, Liqun
Karlsson-Lindahl, Linda
Häger, Ann-Katrin
Weber, Holger
Augustin, Hellmut
Samuelsson, Tore
Kemmet, Chelsy
Utesch, Carly
Essner, Jeffrey
Hackett, Perry
Hellström, Mats
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We combined reverse and chemical genetics to identify targets and compounds modulating blood vessel development. Through transcript profiling in mice, we identified 150 potentially druggable microvessel-enriched gene products. Orthologs of 50 of these were knocked down in a reverse genetic screen in zebrafish, demonstrating that 16 were necessary for developmental angiogenesis. In parallel, 1280 pharmacologically active compounds were screened in a human cell-based assay, identifying 28 compounds selectively inhibiting endothelial sprouting. Several links were revealed between the results of the reverse and chemical genetic screens, including the serine/threonine (S/ T) phosphatases ppp1ca, ppp1cc, and ppp4c and an inhibitor of this gene family; Endothall. Our results suggest that the combination of reverse and chemical genetic screens, in vertebrates, is an efficient strategy for the identification of drug targets and compounds that modulate complex biological systems, such as angiogenesis.

<p>This is a manuscript of an article published as Kalén, Mattias, Elisabet Wallgard, Noomi Asker, Aidas Nasevicius, Elisabet Athley, Erik Billgren, Jon D. Larson et al. "Combination of reverse and chemical genetic screens reveals angiogenesis inhibitors and targets." <em>Chemistry & biology</em> 16, no. 4 (2009): 432-441. doi: <a href="" target="_blank" title="Persistent link using digital object identifier">10.1016/j.chembiol.2009.02.010</a>. Posted with permission.</p>