Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus.
Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus.
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DOI：
10.1083/jcb.200203125
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发表时间：
2002-08-19
期刊：
影响因子：
--
通讯作者：
Lowe JB
中科院分区：
文献类型：
--
作者：
Smith PL;Myers JT;Rogers CE;Zhou L;Petryniak B;Becker DJ;Homeister JW;Lowe JB
糖蛋白岩藻糖基化使Notch跨膜受体的信号转导能够受边缘蛋白调控，有助于选择素依赖性白细胞运输，并且在白细胞黏附缺陷II型（也称为先天性糖基化障碍IIc型，一种以精神运动缺陷、发育异常和白细胞黏附缺陷为特征的罕见人类疾病）中存在缺陷。我们在此报告，在GDP - 岩藻糖合成的从头途径中编码一种酶的FX基因座发生诱导性无效突变的小鼠，表现出几乎完全的细胞岩藻糖基化缺陷，并且子宫内死亡频率因亲本FX基因型而异。存活出生的FX（-/-）小鼠表现出出生后发育不良，通过补充岩藻糖的饮食可抑制这种情况。FX（-/-）成年小鼠患有极度中性粒细胞增多症、骨髓增殖以及白细胞选择素配体表达缺失，类似于LAD - II/CDG - IIc型疾病。通过调节饮食中的岩藻糖为GDP - 岩藻糖合成提供补救途径，可实现白细胞和内皮选择素配体表达、一般细胞岩藻糖基化以及正常出生后生理的相应恢复。对FX（-/-）小鼠岩藻糖基化的条件性控制确定细胞岩藻糖基化事件是生育、早期生长发育和白细胞黏附的必要伴随因素。
Glycoprotein fucosylation enables fringe-dependent modulation of signal transduction by Notch transmembrane receptors, contributes to selectin-dependent leukocyte trafficking, and is faulty in leukocyte adhesion deficiency (LAD) type II, also known as congenital disorder of glycosylation (CDG)-IIc, a rare human disorder characterized by psychomotor defects, developmental abnormalities, and leukocyte adhesion defects. We report here that mice with an induced null mutation in the FX locus, which encodes an enzyme in the de novo pathway for GDP–fucose synthesis, exhibit a virtually complete deficiency of cellular fucosylation, and variable frequency of intrauterine demise determined by parental FX genotype. Live-born FX(−/−) mice exhibit postnatal failure to thrive that is suppressed with a fucose-supplemented diet. FX(−/−) adults suffer from an extreme neutrophilia, myeloproliferation, and absence of leukocyte selectin ligand expression reminiscent of LAD-II/CDG-IIc. Contingent restoration of leukocyte and endothelial selectin ligand expression, general cellular fucosylation, and normal postnatal physiology is achieved by modulating dietary fucose to supply a salvage pathway for GDP–fucose synthesis. Conditional control of fucosylation in FX(−/−) mice identifies cellular fucosylation events as essential concomitants to fertility, early growth and development, and leukocyte adhesion.
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影响因子：
2.7
作者：
FENDERSON, BA;HOLMES, EH;HAKOMORI, S
通讯作者：
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影响因子：
3
作者：
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4
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影响因子：
64.5
作者：
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通讯作者：
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