Abstract
BackgroundAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations affecting UBE3A gene expression. Previous studies in mice revealed distinct critical periods during neurodevelopment in which reactivation of Ube3a gene expression can prevent the onset of behavioral deficits. Whether UBE3A is required for brain function throughout life is unknown. Here, we address the importance of maintaining UBE3A expression after normal brain development.FindingsUsing a conditional mouse, we deleted the Ube3a gene at three ages spanning brain maturation. We assessed the consequences of Ube3a gene deletion by testing the mice in behavioral tasks previously shown to produce robust phenotypes in AS model mice. Early embryonic deletion of Ube3a recapitulated all behavioral deficits of AS mice. In contrast, Ube3a gene deletion at 3 or 12 weeks of age did not have a significant effect on most behavioral tasks and did not increase seizure sensitivity.ConclusionsTaken together, these results emphasize that UBE3A critically impacts early brain development, but plays a more limited role in adulthood. Our findings provide important considerations for upcoming clinical trials in which UBE3A gene expression is reactivated and suggest that even transient UBE3A reinstatement during a critical window of early development is likely to prevent most adverse Angelman syndrome phenotypes. However, sustained UBE3A expression into adulthood is probably needed for optimal clinical benefit.
Highlights
Loss of the maternally inherited Ubiquitin-protein ligase E3A (UBE3A) allele results in Angelman syndrome (AS), a severe neurodevelopmental disorder, which is characterized by severe intellectual disability, motor coordination deficits, absence of speech, abnormal EEG, and behavioral deficits [1]
Our findings provide important considerations for upcoming clinical trials in which UBE3A gene expression is reactivated and suggest that even transient UBE3A reinstatement during a critical window of early development is likely to prevent most adverse Angelman syndrome phenotypes
We demonstrated that Creembryo;Ube3amflox/p+ faithfully recapitulate the phenotypes that we previously established to be present in three independent AS mouse models [18, 19] (Fig. 2, Additional file 4: Table S3, Additional file 5: Figure S2, Additional file 6: Table S4)
Summary
Loss of the maternally inherited UBE3A allele results in Angelman syndrome (AS), a severe neurodevelopmental disorder, which is characterized by severe intellectual disability, motor coordination deficits, absence of speech, abnormal EEG, and behavioral deficits [1]. Paternal UBE3A is silenced in neurons by a long non-coding UBE3A-ATS transcript, which can be activated by either using anti-sense oligonucleotides (ASOs) that target the degradation of this transcript or by topoisomerase inhibitors that interfere with the transcription of the UBE3A-ATS [15,16,17]. Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations affecting UBE3A gene expression.
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