Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development
Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development
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DOI：
10.1242/dev.01037
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发表时间：
2004-04-01
期刊：
影响因子：
4.6
通讯作者：
Mayer, U
中科院分区：
文献类型：
--
作者：
Pöschl, E;Schlötzer-Schrehardt, U;Mayer, U
基底膜是由多种基质分子的组织特异性组织组成的特化细胞外基质，并作为结构屏障以及细胞相互作用的底物。IV型胶原蛋白的网络被认为定义了将其他组分如层粘连蛋白、巢蛋白或串珠素整合到高度组织化的超分子结构中的支架。为了分析主要的IV型胶原亚型α 1（IV）（2）α 2（IV）在基底膜组装和胚胎发育中的功能作用，我们在小鼠中产生了Col 4a 1/2基因座的无效等位基因，从而切除了两条α链。出乎意料的是，胚胎以预期的孟德尔比率发育至E9.5，并表现出不同程度的生长迟缓。基底膜蛋白的沉积和组装在突变体胚胎的预期位点，表明这种亚型是在早期发育过程中的基质沉积和组装。然而，致死性发生在E10.5-E11.5之间，因为基底膜的结构缺陷，并最终由于Reichert膜的完整性失效。这些数据首次表明，胶原蛋白IV是基础的完整性和功能的基底膜的条件下，不断增加的机械需求，但沉积和组件的初始组装。与其他基底膜蛋白敲除一起，这些数据表明，层粘连蛋白在早期发育期间足以形成基底膜样基质，但在后期阶段，包括IV型胶原在内的组分的特定组成决定了完整性、稳定性和功能性。
Basement membranes are specialized extracellular matrices consisting of tissue-specific organizations of multiple matrix molecules and serve as structural barriers as well as substrates for cellular interactions. The network of collagen IV is thought to define the scaffold integrating other components such as, laminins, nidogens or perlecan, into highly organized supramolecular architectures. To analyze the functional roles of the major collagen IV isoform alpha1(IV)(2)alpha2(IV) for basement membrane assembly and embryonic development, we generated a null allele of the Col4a1/2 locus in mice, thereby ablating both a-chains. Unexpectedly, embryos developed up to E9.5 at the expected Mendelian ratio and showed a variable degree of growth retardation. Basement membrane proteins were deposited and assembled at expected sites in mutant embryos, indicating that this isoform is dispensable for matrix deposition and assembly during early development. However, lethality occurred between E10.5-E11.5, because of structural deficiencies in the basement membranes and finally by failure of the integrity of Reichert's membrane. These data demonstrate for the first time that collagen IV is fundamental for the maintenance of integrity and function of basement membranes under conditions of increasing mechanical demands, but dispensable for deposition and initial assembly of components. Taken together with other basement membrane protein knockouts, these data suggest that laminin is sufficient for basement membrane-like matrices during early development, but at later stages the specific composition of components including collagen IV defines integrity, stability and functionality.