Thedy/dymouse is an animal model for human merosin-negative congenital muscular dystrophy (CMD), which has been reported to have reduced or no expression of the basement membrane protein laminin α2. We here investigate various myogenic and nonmyogenic tissues of maturedy/dyand control 129ReJ mice histologically and for laminin α2 expression. In addition, expression patterns of laminin α1, α2, α4, and α5 chains, the interstitial proteins fibronectin and tenascin-C, and the adhesion molecules VCAM-1, ICAM-1, and α4 integrin were characterized in skeletal muscle of 1- and 7-day and mature (>6 weeks old)dy/dyand control 129ReJ mice. The laminin α2 chain remained detectable in myogenic tissues ofdy/dymice by immunofluorescence using two different monoclonal antibodies and by Northern blot analysis. However, laminin α2 expression was significantly reduced or not detectable in nonmyogenic tissues ofdy/dymice, including skin, lung, kidney, brain, thymus, and eye. Focal lesions were observed in mature skeletal muscle only, characterized by necrotic tissue, isolated VCAM-1- and ICAM-1-positive cells indicative of inflammatory processes, and regenerating muscle fibers surrounded by intense tenascin-C and fibronectin expression. In contrast to studies on human CMD muscle, laminin α1 was not detectable in eitherdy/dyor control skeletal muscle using immunofluorescence or Northern blot analysis. Immunofluorescence localized laminin α4 to basement membranes of blood vessels, the endoneurium of the intramuscular nerves, and the neuromuscular junction in skeletal muscle of 1- and 7-day-olddy/dyand control mice. In mature muscle, laminin α4 expression shifted to the perineurium of intramuscular nerves in bothdy/dyand control mice. Furthermore, strong upregulation of laminin α4 in the basement membranes of blood vessels, the perineurium of intramuscular nerves, and of isolated regenerating muscle fibers in thedy/dymice was apparent. Investigation of 1-day-old animals revealed expression of laminin α5 in skeletal muscle fiber basement membranes ofdy/dybut not control animals. This difference betweendy/dyand control animals was no longer apparent at 7 days after birth, indicating a temporary shift in expression pattern of laminin α5 indy/dyanimals. Analysis of the extracellular matrix components of 1- and 7-day-olddy/dyand control skeletal muscle revealed an early onset of the dystrophy, even before histopathological features of the disease were evident. Our data confirm the absence of laminin α1 chain in myogenic tissues of bothdy/dyand control mice and suggest compensation for reduced laminin α2 indy/dyskeletal muscle by laminin α4 and, in early development, also laminin α5. These results have significant ramifications in the diagnosis of human merosin-negative CMD.