Journal
JOURNAL OF NEUROSCIENCE
Volume 38, Issue 2, Pages 363-378Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1511-17.2017
Keywords
ASD; dendritic remodeling; developmental disorder; neuronal development; UBE3A/E6AP; ubiquitination
Categories
Funding
- National Institutes of Health [R01 MH079407]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008541] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH079407] Funding Source: NIH RePORTER
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UBE3A gene copy number variation and the resulting overexpression of the protein E6AP is directly linked to autism spectrum disorders (ASDs). However, the underlying cellular and molecular neurobiology remains less clear. Herewereport the role of ASD-related increased dosage of Ube3A/E6AP in dendritic arborization during brain development. We show that increased E6AP expression in primary cultured neurons leads to a reduction in dendritic branch number and length. The E6AP-dependent remodeling of dendritic arborization results from retraction of dendrites by thinning and fragmentation at the tips of dendrite branches, leading to shortening or removal of dendrites. This remodeling effect is mediated by the ubiquitination and degradation of XIAP (X-linked inhibitors of aptosis protein) by E6AP, which leads to activation of caspase-3 and cleavage of microtubules. In vivo, male and female Ube3A 2X ASD mice show decreased XIAP levels, increased caspase-3 activation, and elevated levels of tubulin cleavage. Consistently, dendritic branching and spine density are reduced in cortical neurons of Ube3A 2X ASD mice. In revealing an important role for Ube3A/E6AP in ASD-related developmental alteration in dendritic arborization and synapse formation, our findings provide new insights into the pathogenesis of Ube3A/E6APdependent ASD.
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