Bonyadi M, Rusholme S A, Cousins F M, Su H C, Biron C A, Farrall M, Akhurst R J
Department of Medical Genetics, Glasgow University, Duncan Guthrie Institute, Yorkhill, UK.
Nat Genet. 1997 Feb;15(2):207-11. doi: 10.1038/ng0297-207.
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.
转化生长因子β1（TGFβ1）信号通路在胚胎发育过程中起着重要作用，并且与遗传性出血性毛细血管扩张症（HHT）、动脉粥样硬化、肿瘤发生及免疫调节有关。因此，识别体内调节TGFβ1生物活性的因子具有重要意义。在混合遗传背景下，约50%的Tgfb1-/-胚胎因卵黄囊血管生成缺陷而在妊娠中期死亡。另一半胚胎发育正常，但在产后三周死亡。有趣的是，Tgfb1-/-小鼠的血管缺陷与HHT患者的病变在组织学上具有相似性。有人提出，Tgfb1-/-致死表型的二分法是由于母体TGFβ1对部分而非全部Tgfb1-/-胚胎的挽救作用。在此，我们表明Tgfb1-/-表型取决于胚胎的遗传背景。在NIH/Ola、C57BL/6J/Ola和F1胚胎中，Tgfb1-/-致死性可分为三个发育类别。利用对产前致死的Tgfb1-/-新生动物中等位基因非孟德尔分布的基因组扫描，将胚胎致死的一个主要共显性修饰基因定位到小鼠近端5号染色体。该基因约占小鼠品系间遗传效应的四分之三，并且可以部分解释三种致死表型的分布。这种使用新生动物DNA样本的方法通常适用于识别影响早期胚胎致死突变效应的基因座，从而增进对体内早期哺乳动物发育过程中发生的遗传相互作用的了解。
