Highwire restrains synaptic growth by attenuating a MAP kinase signal.
Highwire is an extremely large, evolutionarily conserved E3 ubiquitin ligase that negatively regulates synaptic growth at the Drosophila NMJ. Highwire has been proposed to restrain synaptic growth by downregulating a synaptogenic signal. Here we identify such a downstream signaling pathway. A screen for suppressors of the highwire synaptic overgrowth phenotype yielded mutations in wallenda, a MAP kinase kinase kinase (MAPKKK) homologous to vertebrate DLK and LZK. wallenda is both necessary for highwire synaptic overgrowth and sufficient to promote synaptic overgrowth, and synaptic levels of Wallenda protein are controlled by Highwire and ubiquitin hydrolases. highwire synaptic overgrowth requires the MAP kinase JNK and the transcription factor Fos. These results suggest that Highwire controls structural plasticity of the synapse by regulating gene expression through a MAP kinase signaling pathway. In addition to controlling synaptic growth, Highwire promotes synaptic function through a separate pathway that does not require wallenda.
Collins
Catherine A
CA
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Washington University, St. Louis, Missouri 63110, USA.
Wairkar
Yogesh P
YP
Johnson
Sylvia L
SL
DiAntonio
Aaron
A
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology* / Q000254:growth & development; D002874:Chromosome Mapping; D029721:Drosophila Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000196:embryology* / Q000254:growth & development; D005260:Female; D020439:Growth Cones / Q000201:enzymology* / Q000648:ultrastructure; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism; D006867:Hydrolases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013569:Synapses / Q000201:enzymology* / Q000648:ultrastructure; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D029721:Drosophila Proteins; D006131:Growth Inhibitors; C409633:HIW protein, Drosophila; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D044767:Ubiquitin-Protein Ligases; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C512899:wnd protein, Drosophila; D006867:Hydrolases