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¹ International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy
² Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
³ Department of Clinical, Morphological and Technological Sciences, University of Trieste, 34100 Trieste, Italy

Address correspondence to Francisco E. Baralle, International Center for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34012 Trieste, Italy. Tel.: (39) 040-375-7337. Fax: (39) 040-226555. E-mail: baralle{at}icgeb.trieste.it

Fibronectins (FNs) are multifunctional high molecular weight glycoproteins present in the blood plasma and in the ECMs of tissues. The FN primary transcript undergoes alternative splicing in three regions generating up to 20 main different variants in humans. However, the precise role of the FN isoforms is poorly understood. One of the alternatively spliced exons is the extra domain A (EDA) or extra type III homology that is regulated spatially and temporally during development and aging. To study its in vivo function, we generated mice devoid of EDA exon-regulated splicing. Constitutive exon inclusion was obtained by optimizing the splice sites, whereas complete exclusion was obtained after in vivo CRE-loxP–mediated deletion of the exon. Homozygous mouse strains with complete exclusion or inclusion of the EDA exon were viable and developed normally, indicating that the alternative splicing at the EDA exon is not necessary during embryonic development. Conversely, mice without the EDA exon in the FN protein displayed abnormal skin wound healing, whereas mice having constitutive inclusion of the EDA exon showed a major decrease in the FN levels in all tissues. Moreover, both mutant mouse strains have a significantly shorter lifespan than the control mice, suggesting that EDA splicing regulation is necessary for efficient long-term maintenance of biological functions.

Key Words: ECM; integrin receptors; basal lamina; aging; CRE-loxP

The online version of this article includes supplemental material.

^* Abbreviations used in this paper: IIICS, type III homologies connecting segment; EDA, extra domain A; EDB, extra domain B; ES, embryonic stem; cFN, cellular FN; FN, fibronectin; MEF, mouse embryonic fibroblasts; MMP, matrix metalloproteinases; p.c., postcoitus; pFN, plasma FN.

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