Molecular mechanisms that enhance synapse stability despite persistent disruption of the spectrin/ankyrin/microtubule cytoskeleton.
Loss of spectrin or ankyrin in the presynaptic motoneuron disrupts the synaptic microtubule cytoskeleton and leads to disassembly of the neuromuscular junction (NMJ). Here, we demonstrate that NMJ disassembly after loss of alpha-spectrin can be suppressed by expression of a Wld(S) transgene, providing evidence for a Wallerian-type degenerative mechanism. We then identify a second signaling system. Enhanced MAPK-JNK-Fos signaling suppresses NMJ disassembly despite loss of presynaptic alpha-spectrin or ankyrin2-L. This signaling system is activated after an acute cytoskeletal disruption, suggesting an endogenous role during neurological stress. This signaling system also includes delayed, negative feedback via the JNK phosphatase puckered, which inhibits JNK-Fos to allow NMJ disassembly in the presence of persistent cytoskeletal stress. Finally, the MAPK-JNK pathway is not required for baseline NMJ stabilization during normal NMJ growth. We present a model in which signaling via JNK-Fos functions as a stress response system that is transiently activated after cytoskeletal disruption to enhance NMJ stability, and is then shut off allowing NMJ disassembly during persistent cytoskeletal disruption.
Massaro
Catherine M
CM
Department of Biochemistry and Biophysics, Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
Pielage
Jan
J
Davis
Graeme W
GW
D000818:Animals; D030801:Animals, Genetically Modified; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D019085:Fluorescent Antibody Technique, Direct; D007150:Immunohistochemistry; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009469:Neuromuscular Junction / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D013049:Spectrin / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019076:Transgenes
D017487:Ankyrins; D008869:Microtubule-Associated Proteins; D013049:Spectrin