title: Altered social behavior and neuronal development in mice lacking the Uba6-Use1 ubiquitin transfer system.
abstract: The Uba6 (E1)-Use1 (E2) ubiquitin transfer cascade is a poorly understood alternative arm of the ubiquitin proteasome system (UPS) and is required for mouse embryonic development, independent of the canonical Uba1-E2-E3 pathway. Loss of neuronal Uba6 during embryonic development results in altered patterning of neurons in the hippocampus and the amygdala, decreased dendritic spine density, and numerous behavioral disorders. The levels of the E3 ubiquitin ligase Ube3a (E6-AP) and Shank3, both linked with dendritic spine function, are elevated in the amygdala of Uba6-deficient mice, while levels of the Ube3a substrate Arc are reduced. Uba6 and Use1 promote proteasomal turnover of Ube3a in mouse embryo fibroblasts (MEFs) and catalyze Ube3a ubiquitylation in vitro. These activities occur in parallel with an independent pathway involving Uba1-UbcH7, but in a spatially distinct manner in MEFs. These data reveal an unanticipated role for Uba6 in neuronal development, spine architecture, mouse behavior, and turnover of Ube3a.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. peter_lee@hms.harvard.edu
authors.forename: Peter C W
authors.initials: PC
authors.lastname: Lee
authors.forename: Jean-Cosme
authors.initials: JC
authors.lastname: Dodart
authors.forename: Liviu
authors.initials: L
authors.lastname: Aron
authors.forename: Lydia W
authors.initials: LW
authors.lastname: Finley
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Yankner
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
mesh_terms: D000679:Amygdala / Q000002:abnormalities* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D001835:Body Weight; D056654:CA3 Region, Hippocampal / Q000002:abnormalities* / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000473:pathology; D047108:Embryonic Development; D004734:Energy Metabolism; D005260:Female; D005804:Genes, Lethal; D007859:Learning Disabilities / Q000378:metabolism; D008124:Locomotion; D008297:Male; D008569:Memory Disorders / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010101:Oxygen Consumption; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D050767:Qc-SNARE Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D050600:SNARE Proteins; D012919:Social Behavior; D044764:Ubiquitin-Activating Enzymes / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D033921:Vesicular Transport Proteins
chemical_list: C524073:E1-L2 protein, mouse; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D050767:Qc-SNARE Proteins; D050600:SNARE Proteins; C492356:Shank3 protein, mouse; C539363:Use1 protein, mouse; D033921:Vesicular Transport Proteins; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases; D044764:Ubiquitin-Activating Enzymes