title: SkpA restrains synaptic terminal growth during development and promotes axonal degeneration following injury.
abstract: The Wallenda (Wnd)/dual leucine zipper kinase (DLK)-Jnk pathway is an evolutionarily conserved MAPK signaling pathway that functions during neuronal development and following axonal injury. Improper pathway activation causes defects in axonal guidance and synaptic growth, whereas loss-of-function mutations in pathway components impairs axonal regeneration and degeneration after injury. Regulation of this pathway is in part through the E3 ubiquitin ligase Highwire (Hiw), which targets Wnd/DLK for degradation to limit MAPK signaling. To explore mechanisms controlling Wnd/DLK signaling, we performed a large-scale genetic screen in Drosophila to identify negative regulators of the pathway. Here we describe the identification and characterization of SkpA, a core component of SCF E3 ubiquitin ligases. Mutants in SkpA display synaptic overgrowth and an increase in Jnk signaling, similar to hiw mutants. The combination of hypomorphic alleles of SkpA and hiw leads to enhanced synaptic growth. Mutants in the Wnd-Jnk pathway suppress the overgrowth of SkpA mutants demonstrating that the synaptic overgrowth is due to increased Jnk signaling. These findings support the model that SkpA and the E3 ligase Hiw function as part of an SCF-like complex that attenuates Wnd/DLK signaling. In addition, SkpA, like Hiw, is required for synaptic and axonal responses to injury. Synapses in SkpA mutants are more stable following genetic or traumatic axonal injury, and axon loss is delayed in SkpA mutants after nerve crush. As in highwire mutants, this axonal protection requires Nmnat. Hence, SkpA is a novel negative regulator of the Wnd-Jnk pathway that functions with Hiw to regulate both synaptic development and axonal maintenance.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110, and.
authors.forename: E J
authors.initials: EJ
authors.lastname: Brace
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Chunlai
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110, and.
authors.forename: Vera
authors.initials: V
authors.lastname: Valakh
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110, and diantonio@wustl.edu.
authors.forename: Aaron
authors.identifier: http://orcid.org/0000-0002-7262-0968
authors.initials: A
authors.lastname: DiAntonio
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster; D005260:Female; D008297:Male; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology; D044843:SKP Cullin F-Box Protein Ligases / Q000502:physiology*; D013569:Synapses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D029721:Drosophila Proteins; C434749:SkpA protein, Drosophila; D044843:SKP Cullin F-Box Protein Ligases
keywords: Jnk signaling; MAP kinase; Nmnat; PHR ligase; axonal injury response