Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Box 800577, HSC, Charlottesville VA 22908, USA.
Development. 2010 Jan;137(2):249-59. doi: 10.1242/dev.040782.
Tgif1 and Tgif2 are transcriptional co-repressors that limit the response to TGFbeta signaling and play a role in regulating retinoic-acid-mediated gene expression. Mutations in human TGIF1 are associated with holoprosencephaly, but it is unclear whether this is a result of deregulation of TGFbeta/Nodal signaling, or of effects on other pathways. Surprisingly, mutation of Tgif1 in mice results in only relatively mild developmental phenotypes in most strain backgrounds. Here, we show that loss-of-function mutations in both Tgif1 and Tgif2 result in a failure of gastrulation. By conditionally deleting Tgif1 in the epiblast, we demonstrate that a single wild-type allele of Tgif1 in the extra-embryonic tissue allows the double null embryos to gastrulate and begin organogenesis, suggesting that extra-embryonic Tgif function is required for patterning the epiblast. Genetically reducing the dose of Nodal in embryos lacking all Tgif function results in partial rescue of the gastrulation defects. Conditional double null embryos have defects in left-right asymmetry, which are also alleviated by reducing the dose of Nodal. Together, these data show that Tgif function is required for gastrulation, and provide the first clear evidence that Tgifs limit the transcriptional response to Nodal signaling during early embryogenesis.
TGIF1 和 TGIF2 是转录共抑制因子，它们限制了 TGFβ 信号的反应，并在调节维甲酸介导的基因表达中发挥作用。人类 TGIF1 的突变与前脑无裂畸形有关，但尚不清楚这是 TGFβ/Nodal 信号转导失调的结果，还是对其他途径的影响。令人惊讶的是，在大多数背景下，Tgif1 在小鼠中的突变仅导致相对轻微的发育表型。在这里，我们表明 Tgif1 和 Tgif2 的功能丧失突变导致原肠胚形成失败。通过条件性删除外胚层中的 Tgif1，我们证明在胚胎外组织中单个野生型 Tgif1 等位基因允许双 null 胚胎原肠胚形成并开始器官发生，这表明胚胎外 Tgif 功能对于外胚层的模式形成是必需的。在缺乏所有 Tgif 功能的胚胎中遗传降低 Nodal 的剂量会导致原肠胚形成缺陷的部分挽救。条件性双 null 胚胎的左右不对称性缺陷也通过降低 Nodal 的剂量得到缓解。总之，这些数据表明 Tgif 功能对于原肠胚形成是必需的，并提供了第一个明确的证据，表明 Tgifs 在早期胚胎发生过程中限制了对 Nodal 信号的转录反应。
