Susana Wang | PubMed Health

PubMed2005

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.

Animals↗

PubMed2003

Genetic modifiers interact with maternal determinants in vascular development of Tgfb1(-/-) mice.

The transforming growth factor beta signaling family is a key player in genetic and multifactorial diseases, including hereditary hemorrhagic telangiectasia (HHT), cancer, atherosclerosis and immunomodulation. HHT types 1 and 2 are caused by loss of function mutations in ENG and ACVRL1; polymorphisms in TBRI and TGFB1 are also associated with altered risks for cancer and cardiovascular diseases. There is therefore much interest in identifying factors that influence transforming growth factor beta1 (TGFbeta1) action in vivo. Here we identify a potent modifier locus, Tgfbkm2(129) (LOD=10.5, chromosome 1), that contributes over 90% of the genetic component determining survival to birth of Tgfb1(-/-) embryos in crosses between C57 and 129 mice, plus a suggestive modifier locus on chromosome 17 (LOD=3.7). Tgfb1(-/-) survival to birth (STB), in addition to dependence on embryonic Tgfbkm2 genotype, also depends on maternal effects. Fetal genotype and maternal factors interact to prevent Tgfb1(-/-) embryonic death due to defective yolk sac angiogenesis. C57 or C57/129.F1 mothers support high Tgfb1(-/-) STB rates, whereas 129 mothers do not. Strain differences in circulating maternal TGFbeta1 levels were excluded as the cause of this directional complementation. However, strong genetic support is provided for the involvement of maternal STB alleles of mitochondrial or imprinted genes that are only expressed when passed through the female lineage. Molecular identification of the functional gene(s) encoding Tgfbkm2 and its interacting maternal factors will be central to an understanding of the mode of action of TGFbeta1 in cardiovascular development.

Alleles↗