Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells.
Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells.
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DOI：
10.1371/journal.pone.0124649
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lagrange AH
中科院分区：
文献类型：
--
作者：
Grier MD;Carson RP;Lagrange AH
Angelman综合征（AS）是一种以发育迟缓、言语障碍、运动障碍、睡眠障碍和难治性癫痫为特征的严重神经发育障碍。AS是由印迹Ube3a基因编码的Ube3a蛋白丢失引起的。Ube3a在成熟神经元中几乎完全由母体染色体表达。虽然已经很好地描述了脑神经元中的印记，但Ube3a在其他神经组织中的印记和表达仍然相对未被探索。此外，由于AS患者脑功能的巨大缺陷，Ube3a在幕下神经系统中表达中断及其随之而来的残疾的可能性在很大程度上被忽视了。我们评估了Ube3a在脊髓和坐骨神经中的印迹状态，并表明它也在这些神经组织中印迹。此外，越来越多的临床和放射学证据表明，髓鞘功能障碍可能导致许多神经发育综合征的发病率。然而，关于Ube3a在脑的非神经元细胞中的表达的发现有所不同。利用丰富的少突胶质细胞和星形胶质细胞的原代培养物，我们表明，Ube3a的表达，但不印在这些细胞类型。与许多其他神经发育障碍不同，AS症状直到大约6至12个月大时才变得明显。为了确定时间表达模式和沉默，我们分析了AS小鼠在几个时间点的Ube3a表达。我们确认宽松的印记Ube3a的神经元出生后发育皮层，但不是在结构中，神经发生和迁移更完整。这进一步的假设，在AS患者的发展显然是正常的窗口支持一个不完全沉默的父亲等位基因在发展中的神经元，导致在Ube3a表达的相对保存在这个关键时期的早期发展。
Angelman Syndrome (AS) is a devastating neurodevelopmental disorder characterized by developmental delay, speech impairment, movement disorder, sleep disorders and refractory epilepsy. AS is caused by loss of the Ube3a protein encoded for by the imprinted Ube3a gene. Ube3a is expressed nearly exclusively from the maternal chromosome in mature neurons. While imprinting in neurons of the brain has been well described, the imprinting and expression of Ube3a in other neural tissues remains relatively unexplored. Moreover, given the overwhelming deficits in brain function in AS patients, the possibility of disrupted Ube3a expression in the infratentorial nervous system and its consequent disability have been largely ignored. We evaluated the imprinting status of Ube3a in the spinal cord and sciatic nerve and show that it is also imprinted in these neural tissues. Furthermore, a growing body of clinical and radiological evidence has suggested that myelin dysfunction may contribute to morbidity in many neurodevelopmental syndromes. However, findings regarding Ube3a expression in non-neuronal cells of the brain have varied. Utilizing enriched primary cultures of oligodendrocytes and astrocytes, we show that Ube3a is expressed, but not imprinted in these cell types. Unlike many other neurodevelopmental disorders, AS symptoms do not become apparent until roughly 6 to 12 months of age. To determine the temporal expression pattern and silencing, we analyzed Ube3a expression in AS mice at several time points. We confirm relaxed imprinting of Ube3a in neurons of the postnatal developing cortex, but not in structures in which neurogenesis and migration are more complete. This furthers the hypothesis that the apparently normal window of development in AS patients is supported by an incompletely silenced paternal allele in developing neurons, resulting in a relative preservation of Ube3a expression during this crucial epoch of early development.
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