Laminin α1 globular domains 4-5 induce fetal development but are not vital for embryonic basement membrane assembly
Laminin α1 globular domains 4-5 induce fetal development but are not vital for embryonic basement membrane assembly
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DOI：
10.1073/pnas.0405095102
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发表时间：
2005-02-01
影响因子：
11.1
通讯作者：
Ekblom, P
中科院分区：
文献类型：
--
作者：
Schéele, S;Falk, M;Ekblom, P
在小鼠胚胎发育的早期，第一个被描述的层粘连蛋白(LM)的每一条链都是基底膜(BM)组装所必需的，而基底膜是预原肠发育所必需的。单独的域可能有其他功能，不一定是结构性的。Lmα1链的细胞结合C端含有5个Lm球状(LG)结构域。在体外，α1LG1-3结构域与整合素结合，α1LG4与抗肌营养不良聚糖、肝素和硫脂结合。一种流行的假设是，alpha1LG4作为BM组装的结构域是至关重要的，而整合素结合位点负责信号传递。Alpha1LG4-5(也称为E3)在体内的作用还没有研究。因此，建立了缺乏α1LG4-5的小鼠。零胚胎被植入，但推测的上胚细胞未能极化，并在6.5天后不能存活。在Reichert膜中检测到包括截短的Lmα1在内的BM成分。令人惊讶的是，在无效胚胎和α1LG4-5无效胚胎干细胞的类胚体中，内脏内胚层和干细胞之间的胚胎BM组装是正常的。然而，干细胞不能发育成极化的外胚层细胞。因此，Alpha1LG4-5为干细胞向极化上皮的转化提供了重要信号。
During early mouse embryogenesis, each laminin (Lm) chain of the first described Lm, a heterotrimer of alpha1, beta1, and gamma1 chains (Lm-1), is essential for basement membrane (BM) assembly, which is required for pregastrulation development. individual domains may have other functions, not necessarily structural. The cell binding C terminus of Lm alpha1 chain contains five Lm globular (LG) domains. In vitro, alpha1LG1-3 domains bind integrins, and alpha1LG4 binds dystroglycan, heparin, and sulfatides. A prevailing hypothesis is that alpha1LG4 is crucial as a structural domain for BM assembly, whereas integrin-binding sites conduct signaling. The in vivo role of alpha1LG4-5 (also called E3) has not been studied. Mice lacking alpha1LG4-5 were therefore made. Null embryos implanted, but presumptive epiblast cells failed to polarize and did not survive past day 6.5. BM components including truncated Lm alpha1 were detected in Reichert's membrane. Surprisingly, embryonic BM assembly between visceral endoderm and stem cells was normal in null embryos and in embryoid bodies of alpha1LG4-5-null embryonic stem cells. Yet, stem cells could not develop into polarized epiblast cells. Thus, alpha1LG4-5 provides vital signals for the conversion of stem cells to polarized epithelium.