Tgif1 and Tgif2 Regulate Axial Patterning in Mouse.
Tgif1 and Tgif2 Regulate Axial Patterning in Mouse.
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DOI：
10.1371/journal.pone.0155837
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Wotton D
中科院分区：
文献类型：
--
作者：
Melhuish TA;Taniguchi K;Wotton D
Tgif 1和Tgif 2是抑制转化生长因子β信号转导的转录反应的转录抑制因子，并且可以通过直接结合DNA来抑制基因表达。TGIF 1功能缺失突变与人类前脑无裂畸形（HPE）相关。在小鼠中，缺乏Tgif 1和Tgif 2的胚胎不能完成原肠胚形成，而在原肠胚形成后存活的条件性双无效胚胎具有HPE，并且不能存活超过妊娠中期。在这里，我们表明，在一个相对纯的C57 BL/6株背景的小鼠，Tgif 1单独的损失导致有缺陷的轴向图案和Hoxc 6的表达改变。Tgif 1无效胚胎的主要缺陷是C7椎骨上存在额外的肋骨，与后转化表型一致。此外，我们在缺乏Tgif 1的成年小鼠和胚胎中观察到颈椎缺陷，主要是C1-C5。Tgif 1和Tgif 2突变的组合增加了后转化表型的严重性和突变率，而不改变所观察到的缺陷类型。同样，Tgif 1突变胚胎暴露于E8.5维甲酸增加了Tgif 1表型的严重性和突变率。这表明Tgif 1和Tgif 2调节轴向模式，并且TGIF功能降低使胚胎对视黄酸的影响敏感。
Tgif1 and Tgif2 are transcriptional repressors that inhibit the transcriptional response to transforming growth factor β signaling, and can repress gene expression by direct binding to DNA. Loss of function mutations in TGIF1 are associated with holoprosencephaly (HPE) in humans. In mice, embryos lacking both Tgif1 and Tgif2 fail to complete gastrulation, and conditional double null embryos that survive past gastrulation have HPE and do not survive past mid-gestation. Here we show that in mice of a relatively pure C57BL/6 strain background, loss of Tgif1 alone results in defective axial patterning and altered expression of Hoxc6. The primary defects in Tgif1 null embryos are the presence of extra ribs on the C7 vertebra, consistent with a posterior transformation phenotype. In addition we observed defective cervical vertebrae, primarily C1-C5, in both adult mice and embryos that lacked Tgif1. The combination of Tgif1 and Tgif2 mutations increases the severity and penetrance of the posterior transformation phenotype, without altering the type of defects seen. Similarly, exposure of Tgif1 mutant embryos to retinoic acid at E8.5 increased the severity and penetrance of the Tgif1 phenotype. This suggests that Tgif1 and Tgif2 regulate axial patterning and that reduced TGIF function sensitizes embryos to the effects of retinoic acid.