Agrin and synaptic laminin are required to maintain adult neuromuscular junctions.
As synapses form and mature the synaptic partners produce organizing molecules that regulate each other's differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ), these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Here, we used mutant mice to ask whether these organizers are also required for synaptic maintenance. Deletion of agrin from a subset of adult motor neurons resulted in the loss of acetylcholine receptors and other components of the postsynaptic apparatus and synaptic cleft. Nerve terminals also atrophied and eventually withdrew from muscle fibers. On the other hand, mice lacking the presynaptic organizer laminin-α4 retained most of the synaptic cleft components but exhibited synaptic alterations reminiscent of those observed in aged animals. Although we detected no marked decrease in laminin or agrin levels at aged NMJs, we observed alterations in the distribution and organization of these synaptic cleft components suggesting that such changes could contribute to age-related synaptic disassembly. Together, these results demonstrate that pre- and post-synaptic organizers actively function to maintain the structure and function of adult NMJs.
Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States of America.
Melanie A
MA
Samuel
Gregorio
G
Valdez
Juan C
JC
Tapia
Jeff W
JW
Lichtman
Joshua R
JR
Sanes
D018171:Agrin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D007150:Immunohistochemistry; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000502:physiology; D009469:Neuromuscular Junction / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000378:metabolism / Q000502:physiology
D018171:Agrin; C501370:Lama4 protein, mouse; D007797:Laminin