The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology

Hum Mol Genet. 2008 Jan 1;17(1):111-8. doi: 10.1093/hmg/ddm288. Epub 2007 Oct 16.


Loss of function of the maternally inherited allele for the UBE3A ubiquitin ligase gene causes Angelman syndrome (AS), which is characterized by severe neurological impairment and motor dysfunction. In addition, UBE3A lies within chromosome 15q11-q13 region, where maternal, but not paternal, duplications cause autism. The UBE3A gene product, E6-AP, has been shown to function both as an E3 ligase in the ubiquitin proteasome pathway and as a transcriptional coactivator. However, the specific role of E6-AP in the brain, or how loss of function of E6-AP results in AS, is unclear. Herein, we show, using a recombinant transgenic mouse expressing a Ube3a(YFP) fusion gene, that the maternal Ube3a(YFP) allele is upregulated and preferentially expressed in neurons, and that the fusion protein, E6-AP:YFP, is enriched in the nucleus and dendrites in vivo. We also show that E6-AP:YFP localizes to the nucleus and to presynaptic and postsynaptic compartments in cultured hippocampal neurons. Furthermore, we show that cerebellar Purkinje cell number and dendritic branching are not affected in Ube3a maternal-deficient mice, but that dendritic spine development, including spine morphology, number and length, is affected on cerebellar Purkinje cells and on pyramidal neurons in the hippocampus and cortex. Collectively, these data suggest that the neurological deficits observed in AS patients and in AS mice may result from specific abnormalities in synaptic development and/or plasticity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angelman Syndrome / enzymology*
  • Angelman Syndrome / genetics*
  • Angelman Syndrome / pathology
  • Animals
  • Base Sequence
  • Cell Nucleus / enzymology
  • Cells, Cultured
  • DNA Probes / genetics
  • Dendritic Spines / enzymology*
  • Dendritic Spines / pathology*
  • Female
  • Genomic Imprinting
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Synapses / enzymology
  • Ubiquitin-Protein Ligases / deficiency*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*


  • DNA Probes
  • Recombinant Fusion Proteins
  • Ube3a protein, mouse
  • Ubiquitin-Protein Ligases