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Mapping of a major genetic modifier of embryonic lethality in TGFβ1 knockout mice
Abstract
The transforming growth factor beta 1 (TGF beta 1) signalling pathway is important in embryogenesis and has been implicated in hereditary haemorrhagic telangiectasia (HHT), atherosclerosis, tumorigenesis and immunomodulation. Therefore, identification of factors which modulate TGF beta 1 bioactivity in vivo is important. On a mixed genetic background, approximately 50% Tgfb1-/- conceptuses die midgestation from defective yolk sac vasculogenesis. The other half are developmentally normal but die three weeks postpartum. Intriguingly, the vascular defects of Tgfb1-/- mice share histological similarities to lesions seen in HHT patients. It has been suggested that dichotomy in Tgfb1-/- lethal phenotypes is due to maternal TGF beta 1 rescue of some, but not all, Tgfb1-/- embryos12. Here we show that the Tgfb1-/- phenotype depends on the genetic background of the conceptus. In NIH/Ola, C57BL/6J/Ola and F1 conceptuses, Tgfb1-/- lethality can be categorized into three developmental classes. A major codominant modifier gene of embryo lethality was mapped to proximal mouse chromosome 5, using a genome scan for non-mendelian distribution of alleles in Tgfb1-/- neonatal animals which survive prenatal lethality. This gene accounts for around three quarters of the genetic effect between mouse strains and can, in part, explain the distribution of the three lethal phenotypes. This approach, using neonatal DNA samples, is generally applicable to identification of loci that influence the effect of early embryonic lethal mutations, thus furthering knowledge of genetic interactions that occur during early mammalian development in vivo.
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“preclinical studies highlight extensive influences of germline genetic modifiers of TGF-β activity on tumorigenesis, vascular integrity and allergy392,398–400.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [399]
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Metadata
- Authors
- Bonyadi, M., Rusholme, S. A. B., Cousins, F. M., Su, H. C., Biron, C. A., Farrall, M., & Akhurst, R. J.
- Affiliations
- University of Glasgow (GB)
- University of Oxford (GB)
- Brown University (US)
- Centre for Human Genetics (GB)
- Corresponding author
- Akhurst, Rosemary J.
- Venue
- Nature Genetics
- Published
- 1997-02
- Volume
- 15
- Issue
- 2
- Pages
- 207-211
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2064113953
- Cited by
- 166
- References
- 34
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 7 · 2016: 4 · 2015: 2 · 2014: 5 · 2013: 2 · 2012: 7
- FWCI
- 5.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TGF-β1, embryonic lethality, genetic modifiers, hereditary hemorrhagic telangiectasia, chromosome 5, genetic background, genome scan, mouse strains
- MeSH terms
- Animals, Chromosome Mapping, Crosses, Genetic, Fetal Death, Embryonic and Fetal Development, Genes, Lethal, Hematopoiesis, Mice, Inbred C57BL, Phenotype, Yolk Sac, Transforming Growth Factor beta, Mice, Knockout, Microsatellite Repeats, Mice
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