Abstract
BackgroundLaminin α2 chain mutations cause congenital muscular dystrophy with dysmyelination neuropathy (MDC1A). Previously, we demonstrated that laminin α1 chain ameliorates the disease in mice. Dystroglycan and integrins are major laminin receptors. Unlike laminin α2 chain, α1 chain binds the receptors by separate domains; laminin globular (LG) domains 4 and LG1-3, respectively. Thus, the laminin α1 chain is an excellent tool to distinguish between the roles of dystroglycan and integrins in the neuromuscular system.Methodology/Principal FindingsHere, we provide insights into the functions of laminin α1LG domains and the division of their roles in MDC1A pathogenesis and rescue. Overexpression of laminin α1 chain that lacks the dystroglycan binding LG4-5 domains in α2 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 α1LG4-5. However, this domain was crucial for preventing apoptosis in limb muscles, essential for myelination in peripheral nerve and important for basement membrane assembly.Conclusions/SignificanceThese results show that laminin α1LG domains and consequently their receptors have disparate functions in the neuromuscular system. Understanding these interactions could contribute to design and optimization of future medical treatment for MDC1A patients.
Highlights
Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder caused by mutations in the gene encoding laminin (LM) a2 chain
We have previously explored the possibilities of paralogous gene therapy for MDC1A and demonstrated that LMa1 chain is an excellent substitute for LMa2 chain in murine muscle, peripheral nerve and testis [25,26,27,28]
We investigated the roles of LM C-terminal globular domains in muscle and nerve and analyzed the molecular mechanisms underlying LMa1 chain mediated rescue of LMa2 chain deficiency
Summary
Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder caused by mutations in the gene encoding laminin (LM) a2 chain. At least two distinct protein complexes are known to be the key receptors for LMa2 chain; dystroglycan and integrin a7b1. Their importance is underscored by the fact that absence of integrin a7 chain, as well as hypoglycosylation of a-dystroglycan cause various forms of congenital muscular dystrophy [7,8]. Laminin a2 chain mutations cause congenital muscular dystrophy with dysmyelination neuropathy (MDC1A). Dystroglycan and integrins are major laminin receptors. The laminin a1 chain is an excellent tool to distinguish between the roles of dystroglycan and integrins in the neuromuscular system
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