Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model
Sara Silva-Santos, … , Steven A. Kushner, Ype Elgersma
Sara Silva-Santos, … , Steven A. Kushner, Ype Elgersma
Published April 13, 2015
Citation Information: J Clin Invest. 2015;125(5):2069-2076. https://doi.org/10.1172/JCI80554.
View: Text | PDF
Research Article Genetics

Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model

Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal Ube3a allele and determined that there are distinct neurodevelopmental windows during which Ube3a restoration can rescue AS-relevant phenotypes. Motor deficits were rescued by Ube3a reinstatement in adolescent mice, whereas anxiety, repetitive behavior, and epilepsy were only rescued when Ube3a was reinstated during early development. In contrast, hippocampal synaptic plasticity could be restored at any age. Together, these findings suggest that Ube3a reinstatement early in development may be necessary to prevent or rescue most AS-associated phenotypes and should be considered in future clinical trial design.

Authors

Sara Silva-Santos, Geeske M. van Woerden, Caroline F. Bruinsma, Edwin Mientjes, Mehrnoush Aghadavoud Jolfaei, Ben Distel, Steven A. Kushner, Ype Elgersma

×

Figure 1

Embryonic reactivation of Ube3a expression rescues AS-like behavioral phenotypes.

Options: View larger image (or click on image) Download as PowerPoint
Embryonic reactivation of Ube3a expression rescues AS-like behavioral ph...
(A) Schematic representation of Ube3a reactivation (indicated by the gray arrow) during mouse embryonic development and time point of behavioral testing. (B) Western blot analysis of hippocampus (n = 4 per genotype), cortex (n = 5), and cerebellum (n = 5) from Ube3aStop/p+ and WT littermates crossed with an embryonically active Cre line. (C–H) Ube3aStop/p+;Cre– mice show robust behavioral AS-relevant phenotypes, which can be fully rescued by embryonic reactivation of the Ube3a gene in the Ube3aStop/p+;Cre+ mice. Number of mice (WT;Cre+/Ube3aStop/p+;Cre–/Ube3aStop/p+;Cre+): accelerating rotarod, n = 14/8/17; marble burying test, n = 24/18/28; open field test, n = 14/8/17; nest building test, n = 7/7/7; forced swim test, n = 14/8/17; epilepsy test, n = 7/10/8. All data represent mean ± SEM. ANOVA with genotype as independent variable was used for statistical comparisons. A significant effect of genotype was identified in all behavioral tests (see Supplemental Table 1). *P < 0.05, **P < 0.01; Bonferroni’s post hoc analysis.