The agrin hypothesis

UJ McMahan - Cold Spring Harbor symposia on quantitative …, 1990 - symposium.cshlp.org
UJ McMahan
Cold Spring Harbor symposia on quantitative biology, 1990symposium.cshlp.org
The surface of the muscle fiber at vertebrate neuromuscular junctions is characterized by
aggregates of molecules and organdies that, altogether, comprise the postsynaptic
apparatus. Some of these aggregates play a direct role in synaptic transmission and thus
are crucial for neuromuscular function. For example, the plasma membrane of the muscle
fiber has aggregates of receptors (AChRs) for the neurotransmitter, acetylcholine, whereas
the basal lamina of the myofiber has a high concentration of acetylcholinesterase (ACHE) …
The surface of the muscle fiber at vertebrate neuromuscular junctions is characterized by aggregates of molecules and organdies that, altogether, comprise the postsynaptic apparatus. Some of these aggregates play a direct role in synaptic transmission and thus are crucial for neuromuscular function. For example, the plasma membrane of the muscle fiber has aggregates of receptors (AChRs) for the neurotransmitter, acetylcholine, whereas the basal lamina of the myofiber has a high concentration of acetylcholinesterase (ACHE). During the last 20 years, considerable effort has been devoted to understanding how the postsynaptic apparatus forms in the embryo, how it is regulated in the adult, and how it reforms during regeneration. One finding from these studies is that the formation and maintenance of the postsynaptic apparatus is dependent on molecules provided by the axon (for review, see Dennis 1981). Studies conducted in my laboratory have led to the hypothesis that agrin, a protein we have purified and begun to characterize, is such a molecule. The agrin hypothesis (Nitkin et al. 1987; Magill-Solc and McMahan 1988; McMahan and Wallace 1989) is as follows: Agrin, or a protein very similar to it, is synthesized in the cell bodies of motor neurons and transported in their axons to muscle. During embryogenesis, as motor axons approach and grow over the surface of developing myofibers, they release agrin. When agrin binds to an agrin receptor on the myotube surface, it causes AChRs, ACHE, and other components of the postsynaptic apparatus, including components of the synaptic basal lamina, to aggregate on the myotube surface in the vicinity of the activated receptor. Agrin becomes associated with this nascent synaptic basal lamina and thus is bound at the synaptic site, where it can continue to interact with its receptor on the myofiber. Release of agrin from motor nerve terminals at the adult neuromuscular junction and its incorporation into the synaptic basal lamina help maintain the postsynaptic apparatus by ensuring that newly synthesized components become concentrated at the synaptic site, whereas release of agrin by regenerating axons accounts for their ability to induce postsynaptic apparatus at ectopic sites on denervated myofibers. Agrin that persists in basal lamina after myofibers are damaged is believed to account for the ability of the synaptic basal lamina to induce the formation of AChR and AChE aggregates in regenerating muscle fibers, even in the absence of axon terminals, Here, I review the characteristics of agrin and the results of experiments that led to the hypothesis, and I describe recent experiments that have led to and resulted from the cloning of agrin cDNA.
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