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Human Molecular Genetics, 2003, Vol. 12, No. 13 1579-1589
DOI: 10.1093/hmg/ddg164
© 2003 Oxford University Press

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

Yang Tang1, Margaret L. McKinnon1,{dagger}, Li Ming Leong2,{ddagger}, Sarah A. B. Rusholme2,§, Susana Wang1,¶ and Rosemary J. Akhurst1,*

1UCSF Mt Zion Cancer Research Institute, Box 0875, 2340 Sutter Street, San Francisco, CA 94143, USA and 2Duncan Guthrie Institute of Medical Genetics, Glasgow University, Glasgow G3 8SJ, UK

Received March 7, 2003; Accepted April 30, 2003

The transforming growth factor ß 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 ß1 (TGFß1) action in vivo. Here we identify a potent modifier locus, Tgfbkm2129 (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 TGFß1 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 TGFß1 in cardiovascular development.

* To whom correspondence should be addressed. Tel: +1 4155140215; Fax: +1 4155026779; Email: rakhurst{at}cc.ucsf.edu

{dagger} Present address: The University of British Columbia, Medical School, 2329 West Mall Vancouver, BC Canada V6T 1Z4.

{ddagger} Present address: Biomedical Research Council, 250 North Bridge Road, #15-01/02 Raffles City Tower, Singapore 179101.

§ Present address: National Space Centre, Exploration Drive, Leicester, UK.

Present address: Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA.


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