PubMed · 8653780
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R J Kleiman, L F Reichardt. 1996-05-17. Testing the agrin hypothesis.. https://doi.org/10.1016/s0092-8674(00)81245-3
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Congenital muscular dystrophy is a heterogeneous and severe, progressive muscle-wasting disease that frequently leads to death in early childhood. Most cases of congenital muscular dystrophy are caused by mutations in LAMA2, the gene encoding the alpha2 chain of the main laminin isoforms expressed by muscle fibres. Muscle fibre deterioration in this disease is thought to be caused by the failure to form the primary laminin scaffold, which is necessary for basement membrane structure, and the missing interaction between muscle basement membrane and the dystrophin-glycoprotein complex (DGC) or the integrins. With the aim to restore muscle function in a mouse model for this disease, we have designed a minigene of agrin, a protein known for its role in the formation of the neuromuscular junction. Here we show that this mini-agrin-which binds to basement membrane and to alpha-dystroglycan, a member of the DGC-amends muscle pathology by a mechanism that includes agrin-mediated stabilization of alpha-dystroglycan and the laminin alpha5 chain. Our data provides in vivo evidence that a non-homologous protein in combination with rational protein design can be used to devise therapeutic tools that may restore muscle function in human muscular dystrophies.
Agrin is a motoneuron-derived signaling factor that plays a key organizing role in the initial stages of neuromuscular synapse formation. Agrin is expressed in other regions of the developing central and peripheral nervous systems, however, raising the possibility that it also directs the formation of some interneuronal synapses. To address this question, we have examined the expression and localization of agrin during formation of cholinergic, interneuronal synapses in the sympathetic system. In the superior cervical ganglia (SCG) in vivo, we found that agrin is highly expressed, and that it is present at, but is not limited to, synapses. In SCG neuronal cultures that were treated with ciliary neurotrophic factor to induce a uniform cholinergic phenotype, we found that agrin immunostaining colocalized precisely with cholinergic terminals and aggregates of neuronal acetylcholine receptor on the neuronal cell bodies and dendrites. Moreover, we found that alpha-dystroglycan, which is a potential receptor for agrin, is also concentrated at these cholinergic synaptic contacts. Finally, the SCG neurons expressed the C-terminal isoform of agrin that is neural-specific and highly active in synaptogenesis, and also the N-terminal splice isoform that occurs as a type II transmembrane protein. These findings show that agrin is specifically localized at sympathetic synapses in vitro, and are consistent with it playing a role in interneuronal synapse formation.