Epistatic interactions between modifier genes confer strain-specific redundancy for Tgfb1 in developmental angiogenesis.
Tgfbm1 (chromosome 5, P = 8 x 10(-5)) and Tgfbm3 (chromosome 12, P = 6 x 10(-11)) were identified as loci that modify developmental angiogenesis of Tgfb1 -/- mice. Congenic mice validated these loci and demonstrated epistatic interaction between them. The novel locus, Tgfbm3, encompasses approximately 22 genes, colocalizes with both tumor susceptibility and atherosclerosis susceptibility loci, and is enriched in genes regulating cell growth and morphogenesis. The use of gene knockout and/or transgenic mice that predispose to a complex trait, such as vascular development/angiogenesis, facilitates the identification of modifiers by simplifying genetic analysis. Identification of genes that modify response to lack of transforming growth factor beta1 (TGFbeta1) will enhance the understanding of TGFbeta1 action in vivo and may help predict which patients would respond well to anti-TGFbeta therapy. Identification of angiogenesis-modifying genes may provide new targets for angiogenesis therapies and analysis of polymorphisms therein may contribute to assessment of risk for diseases involving angiogenesis.
Tang
Yang
Y
Mt. Zion Cancer Research Institute, University of California, San Francisco, Box 0875, 2340 Sutter Street, Room S231, San Francisco, CA 94143, USA.
Lee
Kyeong Sook
KS
Yang
HaiTao
H
Logan
Darren W
DW
Wang
Susana
S
McKinnon
Margaret L
ML
Holt
Liam J
LJ
Condie
Alison
A
Luu
Minh Thu
MT
Akhurst
Rosemary J
RJ
D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics; D002875:Chromosomes / Q000235:genetics; D004843:Epistasis, Genetic; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease / Q000235:genetics; D008126:Lod Score; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D013045:Species Specificity; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3
C508961:Tgfb1 protein, mouse; C509045:Tgfb3 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3