The mammalian placenta provides a large surface area over which exchange of nutrients and gases between the mother and embryo occurs. Placental insufficiency results in intrauterine growth retardation (IUGR), which is the second leading cause of perinatal death, affecting up to 6% of human pregnancies. There is significant conservation of function between mouse and human placenta, and many of the key regulators are also conserved between the two species. Trophoblast stem (TS) cells give rise to all major cell types of the mouse placenta, and correct TS cell differentiation is required for normal placental development. Retinoic acid (RA) and Nodal signaling have opposing effects on TS cell differentiation: RA signaling promotes the formation of trophoblast giant cells at the expense of spongiotrophoblasts, whereas, Nodal decreases giant cell formation. Disruption of either pathway results in aberrant placental development. Tgif (Thymine Guanine Interacting Factor) is a transcriptional corepressor, which limits both TGF beta/Nodal and RA signaling. Tgif recruits general corepressors to activated Smads, limiting the extent of transcriptional activation by TGF beta/Nodal. Tgif interacts with the RXR retinoic acid receptor and represses RA dependent gene expression. A Tgif null mutation in mice causes placental defects, whereas embryos lacking both Tgif and the functionally related Tgif2 die soon after gastrulation. We will test the hypothesis that Tgifs have critical functions in Nodal and RA signaling at different developmental stages: Complete loss of Tgif and Tgif2 function causes gastrulation defects, primarily by derepressing Nodal regulated gene expression. Later in development, RA signaling is sensitive to reduced Tgif function, and derepression of RA-responsive transcription causes defects in TS cell differentiation and placental development. We will test whether the Tgif mutation alters RA and Nodal signaling, causing defects in placental development. We will test whether Tgif regulates TS cell differentiation in vitro by repressing the transcriptional response of TS cells to RA and Nodal. Finally, we will test whether complete loss of Tgif and Tgif2 function causes defects in gastrulation, by derepressing Nodal-activated gene expression resulting in decreased proliferation and defective axis formation. This will determine how Tgifs regulate placental and embryonic development and generate a better understanding of placental insufficiency, embryonic development and intrauterine growth retardation. ? ? ?
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