MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats
MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats
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DOI：
10.1093/hmg/ddw179
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发表时间：
2016-08-01
影响因子：
3.5
通讯作者：
Olsen, Michelle L.
中科院分区：
文献类型：
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作者：
Patterson, Kelsey C.;Hawkins, Virginia E.;Olsen, Michelle L.
自从在大多数雷特综合征（RTT）病例中确定MECP2为致病基因以来，转基因小鼠模型在我们对这种疾病的理解中发挥了关键作用。使用其他哺乳动物的RTT模型有望进一步阐明疾病的关键早期机制，并为转化研究提供新途径。我们在一种新型的雷特综合征锌指核酸酶模型中，在整个发育过程中对雄性和雌性大鼠进行研究，发现了其生长以及运动和行为功能方面的显著异常。缺乏MeCP2的雄性大鼠（Mecp2(ZFN/y)）早在出生后第21天就有明显症状，大多数在出生后第55天死亡，而缺乏一个Mecp2拷贝的雌性大鼠（Mecp2(ZFN/+)）则表现出更漫长的病程。Mecp2(ZFN/y)和Mecp(2ZFN/+)大鼠的脑重在出生后第14天和第21天分别显著降低。Mecp2(ZFN/y)大鼠早期就出现运动和呼吸异常，而Mecp2(ZFN/+)大鼠在发育后期才表现出功能异常。该物种体型较大，这将在确定早期疾病机制和开发适时的治疗方法方面具有极大优势。当前的研究为在未来的雷特综合征研究中继续使用这种大鼠模型奠定了基础。
Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioural function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2(ZFN/y)) were noticeably symptomatic as early as postnatal day 21, with most dying by postnatal day 55, while females lacking one copy of Mecp2 (Mecp2(ZFN/+)) displayed a more protracted disease course. Brain weights of Mecp2(ZFN/y) and Mecp(2ZFN/+) rats were significantly reduced by postnatal day 14 and 21, respectively. Early motor and breathing abnormalities were apparent in Mecp2(ZFN/y) rats, whereas Mecp2(ZFN/+) rats displayed functional irregularities later in development. The large size of this species will provide profound advantages in the identification of early disease mechanisms and the development of appropriately timed therapeutics. The current study establishes a foundational basis for the continued utilization of this rat model in future RTT research.