Loss of the murine TATA-binding protein N terminus leads to placental labyrinth defects but not maternal adaptive immune responses
Sealey, Amy Lynn.
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The TATA-binding protein (TBP) is a component of the basal transcription machinery. The TBP C-terminal core is conserved in all eukaryotes, but the N terminal region is shared between vertebrates. To study this, we generated a mouse line lacking 111 of the 135 amino acids of the vertebrate-specific sequence. The mutant tbp allele was designated tbp?N, and the majority of homozygous mutants, tbp?N/?N, died at midgestation due to defects in the placenta. Previous studies in our laboratory showed that tbp?N/?N fetuses survived the midgestational crisis if the mother was severely immunocompromised or if mutant fetuses were supplied tbp+/+ placentas. From these data, we hypothesized that the TBP N terminus regulates placental activity that is required for tolerizing the maternal immune system to the conceptus. Recent histological analysis of embryonic day 8.5 (E8.5) to E12.5 placentas in immune wildtype mothers revealed that the tbp?N/?N placental vascular region, or labyrinth, does not develop.In the severely immunocompromised, rag1-deficient mothers, the labyrinth forms, but the vasculature appears to be reduced. Morphometric analysis of E14.5 mutant placentas from rag1-deficient mothers, showed a 2-fold reduction in the number of labyrinth blood vessels. These results suggest that the TBP N Terminus is involved in labyrinth formation and vascularization. Since rag1-deficient mice lack functional B and T cells, we wanted to determine which adaptive immune cells might be involved in the rejection. The tbp?N mouse line was bred to mice lacking various adaptive immune cell subsets to determine which cells were necessary for tbp?N/?N-specific rejection. However, no adaptive immune cell subsets were found to be required for the rejection process. Further maternal immune system characterization via FACS analysis of maternal para-aortic lymph nodes and careful histological analysis showed that maternal adaptive immune cell populations did not change with response to tbp?N/?N fetuses and no adaptive immune cells appeared to infiltrate into the placenta prior to or during rejection. Therefore, the tbp?Nspecific labyrinth malformation is most likely triggering an innate immune pathway.