Magel2 knockout mice manifest altered social phenotypes and a deficit in preference for social novelty.
Magel2 knockout mice manifest altered social phenotypes and a deficit in preference for social novelty.
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DOI：
10.1111/gbb.12378
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Schaaf CP
中科院分区：
文献类型：
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作者：
Fountain MD;Tao H;Chen CA;Yin J;Schaaf CP
MAGEL 2是染色体15 q11-q13上Prader-Willi综合征关键域中的五个蛋白质编码、母系印记、父系表达基因之一。MAGEL 2的截短致病性变体导致Schaaf-Yang综合征（OMIM #615547），一种与Prader-Willi综合征相关的神经发育障碍。受影响的个体表现出一系列神经认知和行为表型，包括智力残疾和自闭症谱系障碍（ASD）。Magel 2基因敲除小鼠携带一个母系遗传的印迹野生型等位基因和一个父系遗传的Magel 2-lacZ敲入等位基因，消除内源性Magel 2基因功能，表现出几个特征，让人联想到人类普拉德-威利表型，包括新生儿生长迟缓，断奶后体重过度增加，并在成年期肥胖增加。他们被证明改变了昼夜节律，减少了运动活动，降低了生育能力。由于ASD在人类患者中的高患病率，因此有必要在该小鼠模型中对自闭症样行为进行广泛评估。通过旷场、高架十字迷宫、试管、三室和分区试验测定Magel 2敲除小鼠及其野生型同窝小鼠的行为。我们的研究证实，在开放领域，雄性和雌性小鼠的水平活动减少，雌性小鼠的垂直活动增加。两种性别的人在高架十字迷宫的开放臂上花的时间都更多，这表明焦虑减少了。两性都表现出缺乏对社会新奇事物的偏好，通过在划分测试中缺乏对已知和新伴侣的区分。对Magel 2功能丧失引起的行为特征的深入研究有助于阐明Schaaf-Yang综合征和Prader-Willi综合征的行为表型的病因。
MAGEL2 is one of five protein-coding, maternally imprinted, paternally expressed genes in the Prader-Willi syndrome-critical domain on chromosome 15q11-q13. Truncating pathogenic variants of MAGEL2 cause Schaaf-Yang syndrome (OMIM #615547), a neurodevelopmental disorder related to Prader-Willi syndrome. Affected individuals manifest a spectrum of neurocognitive and behavioral phenotypes, including intellectual disability and autism spectrum disorder (ASD). Magel2 knockout mice carrying a maternally inherited, imprinted wildtype allele and a paternally inherited Magel2-lacZ knock-in allele, which abolishes endogenous Magel2 gene function, exhibit several features reminiscent of the human Prader-Willi phenotypes, including neonatal growth retardation, excessive weight gain after weaning, and increased adiposity in adulthood. They were shown to have altered circadian rhythm, reduced motor activity, and reduced fertility. An extensive assessment for autism-like behaviors in this mouse model was warranted, due to the high prevalence of ASD in human patients. The behavior of Magel2 knockout mice and their wildtype littermates were assayed via open field, elevated plus maze, tube, three-chamber, and partition tests. Our studies confirm decreased horizontal activity of male and female mice and increased vertical activity of females, in the open field. Both sexes spent more time in the open arm of the elevated plus maze, suggestive of reductions in anxiety. Both sexes displayed a lack of preference for social novelty, via a lack of discrimination between known and novel partners in the partition test. The in-depth investigation of behavioral profiles caused by Magel2 loss-of-function helps to elucidate the etiology of behavioral phenotypes both for Schaaf-Yang syndrome and Prader-Willi syndrome in general.