Background: Laminin a2 chain mutations cause congenital muscular dystrophy with dysmyelination neuropathy (MDC1A). Previously, we demonstrated that laminin a1 chain ameliorates the disease in mice. Dystroglycan and integrins are major laminin receptors. Unlike laminin a2 chain, a1 chain binds the receptors by separate domains; laminin globular (LG) domains 4 and LG1-3, respectively. Thus, the laminin a1 chain is an excellent tool to distinguish between the roles of dystroglycan and integrins in the neuromuscular system. Methodology/Principal Findings: Here, we provide insights into the functions of laminin a1LG domains and the division of their roles in MDC1A pathogenesis and rescue. Overexpression of laminin a1 chain that lacks the dystroglycan binding LG4-5 domains in a2 chain deficient mice resulted in prolonged lifespan and improved health. Importantly, diaphragm and heart muscles were corrected, whereas limb muscles were dystrophic, indicating that different muscles have different requirements for LG4-5 domains. Furthermore, the regenerative capacity of the skeletal muscle did not depend on laminin a1LG4-5. However, this domain was crucial for preventing apoptosis in limb muscles, essential for myelination in peripheral nerve and important for basement membrane assembly. Conclusions/Significance: These results show that laminin a1LG domains and consequently their receptors have disparate functions in the neuromuscular system. Understanding these interactions could contribute to design and optimization o
