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

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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.