agrin

Agrin is a large secreted heparan sulfate proteoglycan encoded by the AGRN gene in humans. It is produced primarily by motor neurons in the peripheral nervous system and by other tissues in different isoforms. Agrin plays a key role in organizing the postsynaptic apparatus at the vertebrate neuromuscular junction.

The protein has an N-terminal domain that binds to alpha-dystroglycan and a C-terminal region containing laminin G-like domains; the gene undergoes extensive alternative splicing to yield neural and muscle isoforms. The neuronal (nerve-derived) isoforms contain an exon cassette called Z inserts; the Z inserts confer strong AChR clustering activity; muscle isoforms lack Z inserts and have reduced activity.

Secreted agrin binds to LRP4 and MuSK on the postsynaptic membrane, activating MuSK and triggering clustering of acetylcholine receptors (AChRs) and the organization of the postsynaptic cytoskeleton; agrin also associates with the dystroglycan-dystrophin complex in the synaptic basal lamina.

Disruption of agrin signaling causes defects in NMJ formation and maintenance; AGRN mutations can cause congenital myasthenic syndromes; autoantibodies against agrin have been reported in some patients with myasthenia gravis; animal models show agrin loss leads to disassembled NMJs and muscle weakness.

Engineered agrin fragments, such as mini-agrin, can promote NMJ formation and have been explored in models of neuromuscular disease. Agrin expression patterns and processing are areas of ongoing study.