In vivo contributions of collagen IV for structure, stability and function of basement membranes

基底膜代表无处不在的细胞外蛋白基质，由网络（层粘连蛋白，胶原蛋白），低聚物（perlecan）和特殊蛋白（nidogens, fibulins）通过许多同源和异二聚体蛋白相互作用连接在一起形成。六个不同的胶原IV亚基链a1(IV)-a6(IV)，以组织特异性的方式聚集成三个不同的网络，形成最重要的结构元件，定义不同基底层的完整性、稳定性和功能。主要亚型a1（IV）和2a2（IV）在所有发育阶段以及成年动物的大多数组织中都有表达，并且被认为是任何发育阶段的基础。为了验证这一假设，我们在小鼠中建立了Col4a1/2位点的敲除模型。应该回答三个主要问题：(1)在没有主要形式的IV型胶原的情况下，基底膜样结构能否形成？(2) IV型胶原对胚胎发育至关重要吗？(3) iv型胶原缺乏对细胞生长、分化和死亡的影响是什么？对iv型胶原蛋白缺陷胚胎的初步分析显示，在胚胎发生早期，基底膜具有意想不到的可塑性，但仍导致胚胎致死性。在其他小鼠模型的背景下分析这个新的模型系统将进一步帮助定义单个基底膜成分的功能。

Basement membranes represent ubiquitous extracellular protein matrices, formed by networks (laminins, collagens IV), oligomers (perlecan) and specialized proteins (nidogens, fibulins) linked together by numerous homo- and heterodimeric protein interactions. Six distinct collagen IV subunit chains, a1(IV)-a6(IV), aggregate into three distinct networks in a tissue-specific manner forming the most important structural elements defining integrity, stability and functionality of different basal laminae. The major isoform a1(IV)2a2(IV) is expressed throughout all stages of development as well as in most tissues of adult animals and was assumed to be fundamental at any stage of development. In order to test this hypothesis, we generated a knock-out model of the Col4a1/2 locus in mice. Three major questions should be answered : (1) Can basement membrane-like structures form in the absence of the major form of collagen IV ? (2) Is collagen IV essential for embryonic development ? and (3) What are the consequences of collagen IV-deficiency on cell growth, differentiation and cell death ? The initial analysis of collagen IV-deficient embryos revealed an unexpected plasticity of basement membranes in early embryogenesis, but nevertheless resulted in embryonic lethality. The analysis of this novel model system in the context with other mouse models will further help to define the functions of individual basement membrane components.