title: Drosophila Valosin-Containing Protein is required for dendrite pruning through a regulatory role in mRNA metabolism.
abstract: The dendritic arbors of the larval Drosophila peripheral class IV dendritic arborization neurons degenerate during metamorphosis in an ecdysone-dependent manner. This process-also known as dendrite pruning-depends on the ubiquitin-proteasome system (UPS), but the specific processes regulated by the UPS during pruning have been largely elusive. Here, we show that mutation or inhibition of Valosin-Containing Protein (VCP), a ubiquitin-dependent ATPase whose human homolog is linked to neurodegenerative disease, leads to specific defects in mRNA metabolism and that this role of VCP is linked to dendrite pruning. Specifically, we find that VCP inhibition causes an altered splicing pattern of the large pruning gene molecule interacting with CasL and mislocalization of the Drosophila homolog of the human RNA-binding protein TAR-DNA-binding protein of 43 kilo-Dalton (TDP-43). Our data suggest that VCP inactivation might lead to specific gain-of-function of TDP-43 and other RNA-binding proteins. A similar combination of defects is also seen in a mutant in the ubiquitin-conjugating enzyme ubcD1 and a mutant in the 19S regulatory particle of the proteasome, but not in a 20S proteasome mutant. Thus, our results highlight a proteolysis-independent function of the UPS during class IV dendritic arborization neuron dendrite pruning and link the UPS to the control of mRNA metabolism.
authors.affiliation: Howard Hughes Medical Institute andDepartments of Physiology andBiochemistry, University of California, San Francisco, CA 94158; and Yuhnung.jan@ucsf.edu sebastian.rumpf@uni-muenster.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rumpf
authors.affiliation: Howard Hughes Medical Institute andDepartments of Physiology andBiochemistry, University of California, San Francisco, CA 94158; and.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bagley
authors.affiliation: Howard Hughes Medical Institute andDepartments of Physiology andBiochemistry, University of California, San Francisco, CA 94158; and.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Thompson-Peer
authors.affiliation: Howard Hughes Medical Institute andDepartments of Physiology andBiochemistry, University of California, San Francisco, CA 94158; and.
authors.forename: Sijun
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Howard Hughes Medical Institute andDepartments of Physiology andBiochemistry, University of California, San Francisco, CA 94158; and.
authors.forename: David
authors.initials: D
authors.lastname: Gorczyca
authors.affiliation: Poultry Science Department, University of Georgia, Athens, GA 30602.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Beckstead
authors.affiliation: Howard Hughes Medical Institute andDepartments of Physiology andBiochemistry, University of California, San Francisco, CA 94158; and.
authors.forename: Lily Yeh
authors.initials: LY
authors.lastname: Jan
authors.affiliation: Howard Hughes Medical Institute andDepartments of Physiology andBiochemistry, University of California, San Francisco, CA 94158; and Yuhnung.jan@ucsf.edu sebastian.rumpf@uni-muenster.de.
authors.forename: Yuh Nung
authors.initials: YN
authors.lastname: Jan
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster / Q000378:metabolism; D004440:Ecdysone / Q000378:metabolism; D005786:Gene Expression Regulation; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C496247:MICAL protein, Drosophila; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C000589036:TBPH protein, Drosophila; D025801:Ubiquitin; D004440:Ecdysone; D046988:Proteasome Endopeptidase Complex; C119011:26S proteasome non-ATPase regulatory subunit 13; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein; C585179:ter94 protein, Drosophila