ABSTRACT
Mammalian TBP consists of a 180 amino acid core that is common to all eukaryotes, fused to a vertebrate-specific N-terminal domain. We generated mice having a modified tbp allele, tbp(DeltaN), that produces a version of TBP lacking 111 of the 135 vertebrate-specific amino acids. Most tbp(DeltaN/DeltaN) fetuses (>90%) died in midgestation from an apparent defect in the placenta. tbp(DeltaN/DeltaN) fetuses could be rescued by supplying them with a wild-type tetraploid placenta. Mutants also could be rescued by rearing them in immunocompromised mothers. In immune-competent mothers, survival of tbp(DeltaN/DeltaN) fetuses increased when fetal/placental beta2m expression was genetically disrupted. These results suggest that the TBP N terminus functions in transcriptional regulation of a placental beta2m-dependent process that favors maternal immunotolerance of pregnancy.
Subject(s)
DNA-Binding Proteins/physiology , Immunity, Maternally-Acquired/immunology , Maternal-Fetal Exchange/immunology , Placenta/immunology , Transcription Factors/physiology , beta 2-Microglobulin/immunology , Alleles , Animals , Animals, Genetically Modified , Binding Sites , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Embryonic and Fetal Development , Evolution, Molecular , Female , Fetus/embryology , Fetus/immunology , Fetus/metabolism , Immune Tolerance , Immunologic Memory , Male , Mice , Mutation , Placenta/metabolism , Placenta/pathology , Placenta/transplantation , Pregnancy , TATA-Box Binding Protein , Transcription Factors/chemistry , Transcription Factors/genetics , beta 2-Microglobulin/biosynthesis , beta 2-Microglobulin/geneticsABSTRACT
Severe combined immunodeficiency (SCID) mice, which lack mature B- and T-cells, provide an important system for studies on immunity and disease. However, since the scid mutation is a single T-to-A transversion, genotypic analysis can be problematic. We have developed a rapid and simple sequence-based analysis that provides identification of both the scid and the wild-type (+) allele. This allows unequivocal identification of scid/scid, scid/+ and +/+ individuals. The method is of greatest utility for discerning scid/+ from +/+ animals during genetic complementation studies, but may be of value for routine SCID colony control as well.
