Distinct roles for laminin globular domains in laminin alpha1 chain mediated rescue of murine laminin alpha2 chain deficiency.
BACKGROUND
Laminin alpha2 chain mutations cause congenital muscular dystrophy with dysmyelination neuropathy (MDC1A). Previously, we demonstrated that laminin alpha1 chain ameliorates the disease in mice. Dystroglycan and integrins are major laminin receptors. Unlike laminin alpha2 chain, alpha1 chain binds the receptors by separate domains; laminin globular (LG) domains 4 and LG1-3, respectively. Thus, the laminin alpha1 chain is an excellent tool to distinguish between the roles of dystroglycan and integrins in the neuromuscular system.


RESULTS
Here, we provide insights into the functions of laminin alpha1LG domains and the division of their roles in MDC1A pathogenesis and rescue. Overexpression of laminin alpha1 chain that lacks the dystroglycan binding LG4-5 domains in alpha2 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 alpha1LG4-5. However, this domain was crucial for preventing apoptosis in limb muscles, essential for myelination in peripheral nerve and important for basement membrane assembly.


CONCLUSIONS
These results show that laminin alpha1LG 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.
Gawlik
Kinga I
KI
Department of Experimental Medical Science, Muscle Biology Unit, University of Lund, Lund, Sweden.
Akerlund
Mikael
M
Carmignac
Virginie
V
Elamaa
Harri
H
Durbeej
Madeleine
M
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D001835:Body Weight / Q000502:physiology; D003402:Creatine Kinase / Q000378:metabolism; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D008124:Locomotion / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism; D017933:Peripheral Nervous System / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology
D015703:Antigens, CD; D039001:Integrin alpha Chains; D007797:Laminin; C085725:integrin alpha7; C102645:laminin alpha 2; D049030:Dystroglycans; C084098:laminin A; D003402:Creatine Kinase