Combination of reverse and chemical genetic screens reveals angiogenesis inhibitors and targets.
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.
Kalén
Mattias
M
AngioGenetics Sweden AB, Scheeles väg 2, SE 171 77 Stockholm, Sweden.
Wallgard
Elisabet
E
Asker
Noomi
N
Nasevicius
Aidas
A
Athley
Elisabet
E
Billgren
Erik
E
Larson
Jon D
JD
Wadman
Shannon A
SA
Norseng
Elizabeth
E
Clark
Karl J
KJ
He
Liqun
L
Karlsson-Lindahl
Linda
L
Häger
Ann-Katrin
AK
Weber
Holger
H
Augustin
Hellmut
H
Samuelsson
Tore
T
Kemmet
Chelsy K
CK
Utesch
Carly M
CM
Essner
Jeffrey J
JJ
Hackett
Perry B
PB
Hellström
Mats
M
D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003998:Dicarboxylic Acids / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish
D020533:Angiogenesis Inhibitors; D003998:Dicarboxylic Acids; C100030:endothall; D010749:Phosphoprotein Phosphatases