Regulation of Placental and Embryonic Development by Tgifs

描述（由申请人提供）：哺乳动物胎盘提供了一个大的表面积，在其上母亲和胚胎之间发生营养和气体交换。胎盘功能不全导致胎儿宫内生长迟缓（IUGR），这是围产期死亡的第二大原因，影响高达6%的人类妊娠。小鼠和人类胎盘之间存在显著的功能保守性，并且两个物种之间的许多关键调控因子也是保守的。滋养层干细胞（TS）产生小鼠胎盘的所有主要细胞类型，并且正常胎盘发育需要正确的TS细胞分化。视黄酸（RA）和Nodal信号对TS细胞分化具有相反的作用：RA信号促进滋养层巨细胞的形成，而Nodal则减少巨细胞的形成。任何一种途径的破坏都会导致异常的胎盘发育。Tgif（胸腺嘧啶鸟嘌呤相互作用因子）是一种转录辅抑制因子，其限制TGF β/Nodal和RA信号传导。Tgif募集一般辅阻遏物以激活Smads，限制TGF β/Nodal的转录激活程度。Tgif与RXR视黄酸受体相互作用并抑制RA依赖性基因表达。小鼠中的Tgif无效突变导致胎盘缺陷，而缺乏Tgif和功能相关的Tgif 2的胚胎在原肠胚形成后不久死亡。我们将测试Tgif在不同发育阶段的Nodal和RA信号传导中具有关键功能的假设：Tgif和Tgif 2功能的完全丧失导致原肠胚形成缺陷，主要是通过去抑制Nodal调节的基因表达。在发育后期，RA信号对Tgif功能降低敏感，RA应答转录的去抑制导致TS细胞分化和胎盘发育缺陷。我们将测试Tgif突变是否改变RA和Nodal信号传导，导致胎盘发育缺陷。我们将测试Tgif是否通过抑制TS细胞对RA和Nodal的转录反应来调节体外TS细胞分化。最后，我们将测试Tgif和Tgif 2功能的完全丧失是否会导致原肠胚形成缺陷，通过去抑制Nodal激活的基因表达导致增殖减少和轴形成缺陷。这将确定Tgif如何调节胎盘和胚胎发育，并更好地了解胎盘功能不全，胚胎发育和宫内生长迟缓。

DESCRIPTION (provided by applicant): 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.