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Molecular and Cellular Biology, July 2004, p. 6049-6057, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.6049-6057.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Development of a Functional Skin Matrix Requires Deposition of Collagen V Heterotrimers

Institut de Biologie et Chimie des Protéines, UMR CNRS 5086, IFR128 BioSciences Lyon-Gerland, 69367 Lyon Cedex 07, France,¹ Laboratory of Genetics and Organogenesis, Hospital for Special Surgery at the Weill College of Medicine of Cornell University, New York, New York 10019²

Received 20 November 2003/ Returned for modification 16 December 2003/ Accepted 2 April 2004

Collagen V is a minor component of the heterotypic I/III/V collagen fibrils and the defective product in most cases of classical Ehlers Danlos syndrome (EDS). The present study was undertaken to elucidate the impact of collagen V mutations on skin development, the most severely affected EDS tissues, using mice harboring a targeted deletion of the 2(V) collagen gene (Col5a2). Contrary to the original report, our studies indicate that the Col5a2 deletion (a.k.a. the pN allele) represents a functionally null mutation that affects matrix assembly through a complex sequence of events. First the mutation impairs assembly and/or secretion of the 1(V)₂2(V) heterotrimer with the result that the 1(V) homotrimer is the predominant species deposited into the matrix. Second, the 1(V) homotrimer is excluded from incorporation into the heterotypic collagen fibrils and this in turn severely impairs matrix organization. Third, the mutant matrix stimulates a compensatory loop by the 1(V) collagen gene that leads to additional deposition of 1(V) homotrimers. These data therefore underscore the importance of the collagen V heterotrimer in dermal fibrillogenesis. Furthermore, reduced thickness of the basement membranes underlying the epidermis and increased apoptosis of the stromal fibroblasts in pN/pN skin strongly indicate additional roles of collagen V in the development of a functional skin matrix.

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