在小鼠视网膜血管生成中,两个NOTCH1 O-fucose位点具有相反的功能
Rachel K LoPilato1, Heike Kroeger2, Sneha K Mohan3
1Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, United States.
Glycobiology
|June 17, 2023
概括
NOTCH1 O-糖糖化对哺乳动物发育至关重要. 影响EGF6和EGF8位点O-基化突变的突变改变了小鼠的视网膜血管生成,影响了Notch信号通路活动和血管网络形成.
科学领域:
- 发展生物学 发展生物学
- 分子生物学分子生物学
- 葡萄糖生物学 葡萄糖生物学
背景情况:
- 在表皮生长因子类重复 (EGFs) 6和8中的O-糖残留中,NOTCH1细胞外域的边缘糖化会影响JAG1和DLL1.1对NOTCH1的激活.
- 这些糖化位点对于调节Notch信号通路活动至关重要.
研究的目的:
- 在哺乳动物发育过程中,研究NOTCH1在EGF6和EGF8中的O-基化在体内的重要性.
- 为了生成和分析具有特定NOTCH1突变影响这些位点O-fucosylation的小鼠模型.
主要方法:
- 产生两种C57BL/6J小鼠线与NOTCH1点突变 (EGF6的T232V,EGF8的T311V),以消除O-化和边缘活动.
- 在生成的小鼠模型中评估视网膜血管生成,包括血管密度和分支.
- 分析与诺奇通路 (Notch1,Jag1,Dll4,Lfng,Mfng,Rfng) 相关的基因表达.
主要成果:
- EGF6 O-fucose突变体 (6f/6f) 呈现了视网膜血管密度和分支的减少,表明Notch1超形态表型.
- EGF8 O-fucose突变小鼠 (8f/8f) 是可行的和肥沃的,表现出增加的视网膜血管密度,与Notch1低形态表型一致.
- 这些发现与关于EGF8突变体生存能力的初始预测形成鲜明对比.
结论:
- NOTCH1 O-糖残留物对于哺乳动物发育过程中正确的途径功能至关重要.
- 在NOTCH1上,特定的O-甘氨酸位含有关键的信号信息,影响视网膜血管生成等发育过程.
- 该研究强调了EGF6和EGF8的O-化对Notch信号结果的不同影响.
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