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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Premature aggregation of type Ⅳ collagen and early lethality in lysyl hydroxylase 3 null mice
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Premature aggregation of type Ⅳ collagen and early lethality in lysyl hydroxylase 3 null mice

机译：赖氨酰羟化酶3无效小鼠的Ⅳ型胶原过早聚集和致死率

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摘要

Collagens carry hydroxylysine residues that act as attachment sites for carbohydrate units and are important for the stability of crosslinks but have been regarded as nonessential for vertebrate survival. We generated mice with targeted inactivation of the gene for one of the three lysyl hydroxylase isoenzymes, LH3. The null embryos developed seemingly normally until embryonic day 8.5, but development was then retarded, with death around embryonic day 9.5. Electron microscopy (EM) revealed fragmentation of basement membranes (BMs), and immuno-EM detected type Ⅳ collagen within the dilated endoplasmic reticulum and in extracellular aggregates, but the typical BM staining was absent. Amorphous intracellular and extracellular particles were also seen by collagen Ⅳ immunofluorescence. SDS/PAGE analysis demonstrated increased mobilities of the type Ⅳ collagen chains, consistent with the absence of hydroxylysine residues and carbohydrates linked to them. These results demonstrate that LH3 is indispensable for biosynthesis of type Ⅳ collagen and for BM stability during early development and that loss of LH3's functions leads to embryonic lethality. We propose that the premature aggregation of collagen Ⅳ is due to the absence of the hydroxylysine-linked carbohydrates, which thus play an essential role in its supramolecular assembly.
机译：胶原蛋白带有羟基赖氨酸残基，这些残基充当碳水化合物单元的附着位点，对交联的稳定性很重要，但被认为对脊椎动物的生存至关重要。我们生成了针对小鼠的三种赖氨酰羟化酶同工酶LH3的基因，使其具有针对性的灭活小鼠。空胚似乎在胚胎第8.5天之前发育正常，但随后发育受阻，在胚胎第9.5天左右死亡。电子显微镜（EM）显示基底膜（BMs）断裂，免疫EM检测到扩张的内质网内和细胞外聚集物中的Ⅳ型胶原，但典型的BM染色不存在。 Ⅳ型胶原免疫荧光还观察到非晶的细胞内和细胞外颗粒。 SDS / PAGE分析表明，Ⅳ型胶原链的运动性增加，这与缺乏羟基赖氨酸残基和与其相连的碳水化合物一致。这些结果表明LH3对于Ⅳ型胶原的生物合成和早期发育期间的BM稳定性是必不可少的，并且LH3功能的丧失导致胚胎致死性。我们认为胶原蛋白Ⅳ过早聚集是由于缺乏羟赖氨酸连接的碳水化合物，因此在其超分子组装中起着至关重要的作用。

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