Female Mecp2± mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies
Female Mecp2± mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies
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DOI：
10.1093/hmg/dds406
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发表时间：
2013-01-01
影响因子：
3.5
通讯作者：
Zoghbi, Huda Y.
中科院分区：
文献类型：
--
作者：
Samaco, Rodney C.;McGraw, Christopher M.;Zoghbi, Huda Y.
Rett综合征(RTT)是一种X连锁的神经系统疾病，由编码转录调节因子甲基CpG结合蛋白2(MeCP2)的基因突变引起。典型的RTT主要影响女孩，其特征是明显正常的短暂发育，随后丧失有目的的手技能和语言，出现焦虑、手的刻板印象、自闭症特征、癫痫发作和自主神经功能障碍。MeCP2小鼠模型已经被广泛研究，以证明MeCP2功能障碍与RTT发病机制之间的功能联系。然而，大多数研究主要集中在雄性小鼠完全缺乏MeCP2的分子和行为后果上。对雌性MeCP2(/)小鼠的研究一直受到限制，因为X染色体失活效应可能导致表型变异。为了确定MeCP2(/)小鼠是否可以检测到可重复和可靠的表型，我们用几种神经行为和生理分析方法分析了两个不同F1杂交种等基因背景和年轻和老年的MeCP2(/)小鼠。在这里，我们报告了雌性MeCP2(/)小鼠的多种表型，其中一些在5周大的时候就出现了。我们证明了MeCP2(/)小鼠概括了典型RTT的几个方面，并表明MeCP2的嵌合体表达并不排除将雌性小鼠用于行为和分子研究。重要的是，我们发现了存在于两种遗传背景中的几种行为异常，并报告了一种背景特有的表型。这些发现为旨在改善RTT小鼠模型表型星座的临床前研究提供了一个框架。
Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Typical RTT primarily affects girls and is characterized by a brief period of apparently normal development followed by the loss of purposeful hand skills and language, the onset of anxiety, hand stereotypies, autistic features, seizures and autonomic dysfunction. Mecp2 mouse models have extensively been studied to demonstrate the functional link between MeCP2 dysfunction and RTT pathogenesis. However, the majority of studies have focused primarily on the molecular and behavioral consequences of the complete absence of MeCP2 in male mice. Studies of female Mecp2(/) mice have been limited because of potential phenotypic variability due to X chromosome inactivation effects. To determine whether reproducible and reliable phenotypes can be detected Mecp2(/) mice, we analyzed Mecp2(/) mice of two different F1 hybrid isogenic backgrounds and at young and old ages using several neurobehavioral and physiological assays. Here, we report a multitude of phenotypes in female Mecp2(/) mice, some presenting as early as 5 weeks of life. We demonstrate that Mecp2(/) mice recapitulate several aspects of typical RTT and show that mosaic expression of MeCP2 does not preclude the use of female mice in behavioral and molecular studies. Importantly, we uncover several behavioral abnormalities that are present in two genetic backgrounds and report on phenotypes that are unique to one background. These findings provide a framework for pre-clinical studies aimed at improving the constellation of phenotypes in a mouse model of RTT.