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首页> 外文期刊>Molecular and Cellular Biology >Ogt-Dependent X-Chromosome-Linked Protein Glycosylation Is a Requisite Modification in Somatic Cell Function and Embryo Viability
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Ogt-Dependent X-Chromosome-Linked Protein Glycosylation Is a Requisite Modification in Somatic Cell Function and Embryo Viability

机译：Ogt依赖X染色体连锁的蛋白质糖基化是体细胞功能和胚胎生存能力的必要修饰。

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The Ogt gene encodes a glycosyltransferase that links N-acetylglucosamine to serine and threonine residues (O-GlcNAc) on nuclear and cytosolic proteins. Efforts to study a mammalian model of Ogt deficiency have been hindered by the requirement for this X-linked gene in embryonic stem cell viability, necessitating the use of conditional mutagenesis in vivo. We have extended these observations by segregating Ogt mutation to distinct somatic cell types, including neurons, thymocytes, and fibroblasts, the latter by an approach developed for inducible Ogt mutagenesis. We show that Ogt mutation results in the loss of O-GlcNAc and causes T-cell apoptosis, neuronal tau hyperphosphorylation, and fibroblast growth arrest with altered expression of c-Fos, c-Jun, c-Myc, Sp1, and p27. We further segregated the mutant Ogt allele to parental gametes by oocyte- and spermatid-specific Cre-loxP mutagenesis. By this we established an in vivo genetic approach that supports the ontogeny of female heterozygotes bearing mutant X-linked genes required during embryogenesis. Successful production and characterization of such female heterozygotes further indicates that mammalian cells commonly require a functional Ogt allele. We find that O-GlcNAc modulates protein phosphorylation and expression among essential and conserved cell signaling pathways.
机译： Ogt 基因编码一个糖基转移酶，该酶将 N -乙酰氨基葡萄糖与核蛋白和胞质蛋白上的丝氨酸和苏氨酸残基（O-GlcNAc）连接起来。在胚胎干细胞活力中对这种X连锁基因的需求阻碍了研究 Ogt 缺乏症的哺乳动物模型的努力，因此必须在体内使用条件诱变技术。我们通过将 Ogt 突变分离到不同的体细胞类型，包括神经元，胸腺细胞和成纤维细胞，扩展了这些观察结果，后者通过可诱导的 Ogt 诱变方法开发。我们显示， Ogt 突变导致O-GlcNAc丢失，并导致T细胞凋亡，神经元tau过度磷酸化和成纤维细胞生长停滞，并改变c-Fos，c-Jun，c-Myc的表达，Sp1和p27。通过卵母细胞和精子特异的Cre- loxP 诱变，我们进一步将突变的 Ogt 等位基因分离到亲本配子。通过这种方法，我们建立了一种体内遗传学方法，该方法可支持雌性杂合子的个体发育，该杂合子带有在胚胎发生过程中所需的突变X连锁基因。此类雌性杂合子的成功生产和表征进一步表明，哺乳动物细胞通常需要功能性 Ogt 等位基因。我们发现O-GlcNAc调节蛋白质磷酸化和必要和保守的细胞信号通路之间的表达。

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