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Altered social behavior and neuronal development in mice lacking the Uba6-Use1 ubiquitin transfer system.

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.

Pubmed ID: 23499007


  • Lee PC
  • Dodart JC
  • Aron L
  • Finley LW
  • Bronson RT
  • Haigis MC
  • Yankner BA
  • Harper JW


Molecular cell

Publication Data

April 25, 2013

Associated Grants

  • Agency: NIA NIH HHS, Id: AG011085
  • Agency: NIA NIH HHS, Id: DP1 AG044161
  • Agency: NIA NIH HHS, Id: R01 AG011085

Mesh Terms

  • Amygdala
  • Animals
  • Body Weight
  • CA3 Region, Hippocampal
  • Cells, Cultured
  • Dendritic Spines
  • Embryonic Development
  • Energy Metabolism
  • Female
  • Genes, Lethal
  • Learning Disorders
  • Locomotion
  • Male
  • Memory Disorders
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins
  • Oxygen Consumption
  • Protein Stability
  • Protein Structure, Tertiary
  • Qc-SNARE Proteins
  • Social Behavior
  • Ubiquitin-Activating Enzymes
  • Ubiquitin-Protein Ligases
  • Ubiquitination