Strain-Dependent Variation in Developmental TGFbeta1 Knockout Phenotypes

The transforming growth factors Beta (TGP?) comprise three closely-related polypeptides with non-overlapping functions in vivo. On a mixed genetic background, a proportion of mice homozygous null and heterozygous for a targeted disruption in their TGFbeta1 gene die pre-natally with defects in yolk sac haematopoiesis and vasculogenesis (Dickson et al., 1995). In this project, the variable penetrance of lethality in TGFbeta1 knockouts was investigated. The TGFbeta1 null allele was bred to 93.75% purity in different inbred strains of mice, and the gross morphology and histology of TGFbeta1+/- intercross litters from these backgrounds was examined at different pre- and post-natal stages. Molecular aspects of the abnormal mid-gestation phenotype were analysed. The lethal phenotype of the TGFbeta1 knockout was clearly strain-dependent - and the variable expressivity and penetrance of the observed phenotypes in TGFbeta1+/- and TGFbeta1-/- conceptuses suggested three critical stages when TGFbeta1 is essential: a) preorganogenesis; b) in the establishment of a stable extra-embryonic vasculature and during haemoglobinisation of primitive erythroid precursors; c) post-natally as an immunomodulator. This study shows that a combination of genetic and environmental factors interact to produce the TGFbeta1 knockout phenotypes