Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal UBE3A allele. Promising treatment strategies for AS are directed at activating paternal UBE3A gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development. Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development. Ube3a gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal Ube3a allele was deleted. We observed a full behavioral rescue of the AS mouse model phenotypes when Ube3a gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal Ube3a allele was not completed till the first week after birth but that deletion of the paternal Ube3a allele had no significant effect on the assessed phenotypes. Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown. Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21.

中文翻译：

---

评估产前 UBE3A 表达对拯救 Angelman 综合征小鼠模型中行为表型的要求。

Angelman 综合征 (AS) 是一种罕见的神经发育障碍，由功能性泛素蛋白连接酶 E3A (UBE3A) 缺失引起。在神经元中，UBE3A 表达受到抑制父本 UBE3A 等位基因表达的印记机制的严格调控。有希望的 AS 治疗策略旨在激活父本 UBE3A 基因表达。然而，要使此类策略取得成功，重要的是要了解此类治疗应何时开始，以及正常胚胎大脑发育需要多少 UBE3A 表达。使用 AS 的条件小鼠模型，我们进一步描绘了早期大脑发育过程中 UBE3A 表达的关键时期。Ube3a 基因表达在妊娠第二周左右被诱导，并使用行为测试电池评估小鼠表型。为了研究胚胎 UBE3A 表达的要求，我们使用了父系 Ube3a 等位基因被删除的小鼠。当 Ube3a 基因重新激活在小鼠胚胎发育的最后一周开始时被诱导时，我们观察到 AS 小鼠模型表型的完整行为拯救。我们发现父本 Ube3a 等位基因的完全沉默直到出生后第一周才完成，但父本 Ube3a 等位基因的缺失对评估的表型没有显着影响。直接转化为人类是有限的，因为我们并不确切知道人类和小鼠的大脑发育如何随着妊娠时间而对齐。此外，许多评估的表型的转化价值有限，因为参与这些任务的潜在大脑区域在很大程度上是未知的。我们的发现为大脑发育过程中 UBE3A 表达的需求提供了进一步的重要见解。我们发现在产前小鼠大脑发育过程中丢失高达 50% 的 UBE3A 蛋白不会显着影响评估的小鼠行为表型。与之前的研究结果一起，我们的结果表明小鼠 UBE3A 最关键的功能在于出生和 P21 之间的产后早期。