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Cell Res:中科院遗传所张永清和李晓江研究组发表自闭症的非人灵长类模型研究论文

摘要 : 2017年7月25日,国际学术权威刊物自然出版集团旗下子刊《Cell Research》杂志在线发表了中国科学院遗传与发育生物学研究所张永清研究组、李晓江研究组,美国杜克大学医学院教授姜永辉团队和华中科技大学教授鲁友明团队,以及广州元㬢生物科技有限公司密切合作的一篇论文,

2017年7月25日,国际学术权威刊物自然出版集团旗下子刊《Cell Research》杂志在线发表了中国科学院遗传与发育生物学研究所张永清研究组、李晓江研究组,美国杜克大学医学院教授姜永辉团队和华中科技大学教授鲁友明团队,以及广州元㬢生物科技有限公司密切合作的一篇论文,研究论文报道了自闭症的非人灵长类模型研究进展。张永清组博士研究生赵晖为本文的第一作者,李晓江实验室博士涂著池为共同第一作者。

自闭症谱系障碍(ASD)儿童表现出社交障碍,刻板重复行为和兴趣狭隘等行为学特征。流行病学研究表明,世界范围内大约1%的儿童表现有ASD。大量基础研究使用遗传修饰小鼠深入分析ASD的病理学机制。然而,小鼠和人类在大脑结构和行为学特征上存在巨大差异,严重影响小鼠模型研究的临床转化价值。因此,有必要开发相应的ASD非人灵长类模型,促进基础研究成果的临床转化。

SHANK3基因突变在ASD病人中出现频率最高,是目前国际上公认的几个ASD高发致病基因之一。研究组使用CRISPR/Cas9编辑技术在食蟹猴胚胎中打靶SHANK3基因,制备基因突变猴后代,最终获得了三只带有SHANK3基因突变的食蟹猴后代。SHANK3完全缺失导致一些突触后电子致密区蛋白如GluN2B、PSD95和mGluR5显著下调,以及Homer1b/c的异常亚细胞定位。在负责高级认知功能和社交行为的大脑前额叶区域,研究人员发现突变猴的成熟神经元数目显著降低,而星形胶质细胞显著增加。突变猴的前额叶皮层神经元的树突棘密度也显著降低。由于SHANK3缺失的小鼠模型未表现出上述病理变化,这些结果表明SHANK3特异性调控灵长类胚胎大脑发育。

ASD基因是否和如何影响大脑发育是ASD领域关注的重大科学问题。之前的研究由于人脑材料样本的限制,不能直接回答特定ASD基因是否影响人的大脑发育。本项研究为理解ASD的神经病理发生机制提供了新的视野,也揭示了非人灵长类动物模型在研究ASD病理机制中的重要性和必要性。

SHANK3缺失导致猴脑皮层发育异常,神经元数目减少,胞体变小,星形胶质细胞增多。

原文链接:

Altered neurogenesis and disrupted expression of synaptic proteins in prefrontal cortex of SHANK3-deficient non-human primate

原文摘要:

Despite substantial progress made toward understanding the molecular changes contributing to autism spectrum disorders (ASD), the neuropathophysiology underlying ASD remains poorly understood1,2. Structural brain imaging in humans is valuable, but lacks resolution at the cellular level. Studies of neuropathology in humans have been hampered by the lack of high quality postmortem brains from individuals with ASD2. For more than decades, mutant mice have served as major tools to dissect the pathophysiology of ASD because of the wealth of molecular and neurobiological techniques developed for studies with rodents. Our knowledge of molecular and cellular mechanisms for ASD is mostly limited to what we have learned from genetically modified mice. However, there are significant evolutionary differences in brain structure and behavior between rodents and humans. For example, social behaviors and the organization of cerebral cortex differ significantly between primates and rodents. The cerebral neocortex comprises ~80% of the human brain and ~72% of the macaque brain, but only ~28% of the rat brain. Prefrontal cortex (PFC), a critical region for high order cognitive and social functions, is under-developed in rodents compared with primates. The unique behavioral features in human ASD have posed significant challenges to assess the translational value of many findings from ASD mouse models. The apparent evolutionary differences in brain structures and behaviors between mouse and human highlight the need of alternative animal models such as non-human primate models for ASD3. The value of a primate model to study ASD has been supported by the generation and characterization of monkeys with altered expressions of MECP2 using the lentivirus- and TALEN-based method4,5.

来源: Cell Research 浏览次数:0

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