Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism.
Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism.
复制标题
自闭症中观察到的人类15q11-13重复的染色体工程小鼠模型中的异常行为。
DOI：
10.1016/j.cell.2009.04.024
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发表时间：
2009-06-26
期刊：
影响因子：
64.5
通讯作者：
Takumi T
中科院分区：
文献类型：
--
作者：
Nakatani J;Tamada K;Hatanaka F;Ise S;Ohta H;Inoue K;Tomonaga S;Watanabe Y;Chung YJ;Banerjee R;Iwamoto K;Kato T;Okazawa M;Yamauchi K;Tanda K;Takao K;Miyakawa T;Bradley A;Takumi T
大量证据表明，染色体异常有助于自闭症的风险。已知人类染色体15 q11 -13的复制是自闭症中最常见的细胞遗传学异常。我们通过使用染色体工程在小鼠7号染色体上产生6.3 Mb重复的保守连锁群，在小鼠中模拟了这种遗传变化。具有父系重复的小鼠表现出不良的社会互动、行为稳定性、异常超声发声和焦虑相关性。增加MBII 52 snoRNA内的复制区域，影响5-羟色胺2c受体（5-HT 2cR），与改变细胞内Ca 2+的反应引起的5-HT 2cR激动剂在小鼠的神经元与父亲重复。这种染色体工程自闭症小鼠模型似乎复制了人类自闭症表型的各个方面，并验证了人类染色体异常的相关性。该模型将促进发育性脑疾病的正向遗传学，并作为治疗开发的宝贵工具。
Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca2+ responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.
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