O-fucosylation of thrombospondin type 1 repeats restricts epithelial to mesenchymal transition (EMT) and maintains epiblast pluripotency during mouse gastrulation.
O-fucosylation of thrombospondin type 1 repeats restricts epithelial to mesenchymal transition (EMT) and maintains epiblast pluripotency during mouse gastrulation.
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DOI：
10.1016/j.ydbio.2010.07.008
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发表时间：
2010-10-01
影响因子：
2.7
通讯作者：
Holdener BC
中科院分区：
文献类型：
--
作者：
Du J;Takeuchi H;Leonhard-Melief C;Shroyer KR;Dlugosz M;Haltiwanger RS;Holdener BC
血小板反应蛋白 1 型重复序列 (TSR) 超家族成员调节多种生物活性，从细胞运动到抑制血管生成。在这项研究中，我们验证了小鼠蛋白 O-岩藻糖基转移酶-2 (POFUT2) 特异性地将 O-岩藻糖添加到 TSR 中。使用两个 Pofut2 基因捕获系，我们证明 TSR 的 O-岩藻糖基化对于限制原条中上皮到间质的转变、中胚层的正确模式以及定形内胚层的定位至关重要。尽管Pofut2突变胚胎建立了前/后极性，但它们经历了广泛的中胚层分化，但以维持外胚层多能性为代价。此外，中胚层分化偏向血管内皮细胞谱系。 Foxa2 和 Cer1 表达细胞在 Pofut2 突变体胚胎内部的定位表明，POFUT2 活性也是定形内胚层取代原始内胚层所必需的。值得注意的是，Nodal、BMP4、Fgf8 和 Wnt3 的表达在 Pofut2 突变体中显着升高和扩展，这提供了 TSR 的 O-岩藻糖修饰对于原肠胚形成过程中生长因子信号传导的调节至关重要的证据。 Pofut2突变胚胎形成由所有三个胚层起源的组织组成的畸胎瘤的能力表明Pofut2突变胚胎的缺陷是由细胞外环境异常引起的。该预测与 POFUT2 靶点是细胞外基质 (ECM) 的组成部分或与 ECM 相关的观察结果一致。因此，Pofut2突变体是研究O-岩藻糖基化在ECM合成和重塑中的作用的一个有价值的工具，并且将成为研究ECM成分的翻译后修饰如何调节组织边界、细胞运动和信号传导的形成的一个有价值的模型。
Thrombospondin type 1 repeat (TSR) superfamily members regulate diverse biological activities ranging from cell motility to inhibition of angiogenesis. In this study, we verified that mouse protein O-fucosyltransferase-2 (POFUT2) specifically adds O-fucose to TSRs. Using two Pofut2 gene trap lines, we demonstrated that O-fucosylation of TSRs was essential for restricting epithelial to mesenchymal transition in the primitive streak, correct patterning of mesoderm, and localization of the definitive endoderm. Although Pofut2 mutant embryos established anterior/posterior polarity, they underwent extensive mesoderm differentiation at the expense of maintaining epiblast pluripotency. Moreover, mesoderm differentiation was biased towards the vascular endothelial cell lineage. Localization of Foxa2 and Cer1 expressing cells within the interior of Pofut2 mutant embryos suggested that POFUT2 activity was also required for the displacement of the primitive endoderm by definitive endoderm. Notably, Nodal, BMP4, Fgf8, and Wnt3 expression were markedly elevated and expanded in Pofut2 mutants, providing evidence that O-fucose modification of TSRs was essential for modulation of growth factor signaling during gastrulation. The ability of Pofut2 mutant embryos to form teratomas comprised of tissues from all three germ layer origins suggested that defects in Pofut2 mutant embryos resulted from abnormalities in the extracellular environment. This prediction is consistent with the observation that POFUT2 targets are constitutive components of the extracellular matrix (ECM) or associate with the ECM. For this reason, the Pofut2 mutants represent a valuable tool for studying the role of O-fucosylation in ECM synthesis and remodeling, and will be a valuable model to study how post-translational modification of ECM components regulates the formation of tissue boundaries, cell movements, and signaling.
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DOI：
10.1083/jcb.138.3.707
发表时间：
1997-08-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dawson DW;Pearce SF;Zhong R;Silverstein RL;Frazier WA;Bouck NP
通讯作者：
Bouck NP
影响因子：
4.8
作者：
Hess, Daniel;Keusch, Jeremy J.;Hofsteenge, Jan
通讯作者：
Hofsteenge, Jan
影响因子：
64.8
作者：
Brennan, J;Lu, CC;Robertson, EJ
通讯作者：
Robertson, EJ
影响因子：
5.3
作者：
Fiore, R;Rahim, B;Püschell, AW
通讯作者：
Püschell, AW
影响因子：
11.8
作者：
Ben-Haim, Nadav;Lu, Cindy;Constam, Daniel B.
通讯作者：
Constam, Daniel B.