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.
Tang
Yang
Y
UCSF Mt Zion Cancer Research Institute, Box 0875, 2340 Sutter Street, San Francisco, CA 94143, USA.
McKinnon
Margaret L
ML
Leong
Li Ming
LM
Rusholme
Sarah A B
SA
Wang
Susana
S
Akhurst
Rosemary J
RJ
D000483:Alleles; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002470:Cell Survival; D003433:Crosses, Genetic; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008126:Lod Score; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009035:Mothers; D011110:Polymorphism, Genetic; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics*
D005819:Genetic Markers; D016212:Transforming Growth Factor beta