Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion
Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion
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DOI：
10.1073/pnas.1615719114
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发表时间：
2017-07-25
影响因子：
11.1
通讯作者：
Gogos, Joseph A.
中科院分区：
文献类型：
--
作者：
Diamantopoulou, Anastasia;Sun, Ziyi;Gogos, Joseph A.
保护性功能丧失（LoF）突变的识别为设计新型治疗干预措施带来了巨大希望，尽管由于人类基因组中保护性 LoF 等位基因的稀缺而面临挑战。利用已验证疾病突变的动物模型的详细机制特征提供了另一种选择。在这里，我们根据 22q11.2 缺失（精神分裂症 (SCZ) 的一个强遗传风险因素）模型的表征，提供了对保护性变异生物学的见解。出生后大脑中 Mirta22/Emc10（一种神经元成熟抑制剂）的上调代表了 22q11.2 相关 microRNA 失调的主要转录效应。在这里，我们证明，Df(16)A 缺陷与 LoF Mirta22 等位基因相结合的小鼠可以挽救与 SCZ 相关的关键缺陷，即前脉冲抑制减少、工作记忆损伤和社会记忆缺陷，以及前额叶皮层的突触和结构可塑性异常。对纯合 Mirta22 敲除小鼠的额外分析强调了 Mirta22 上调的有害影响，其中未观察到上述 SCZ 相关表型的改变。我们的结果支持 miRNA 靶点失调与 SCZ 相关缺陷之间的因果关系，并为有益的 LoF 突变和潜在的新疗法提供了重要见解。
Identification of protective loss-of-function (LoF) mutations holds great promise for devising novel therapeutic interventions, although it faces challenges due to the scarcity of protective LoF alleles in the human genome. Exploiting the detailed mechanistic characterization of animal models of validated disease mutations offers an alternative. Here, we provide insights into protective-variant biology based on our characterization of a model of the 22q11.2 deletion, a strong genetic risk factor for schizophrenia (SCZ). Postnatal brain up-regulation of Mirta22/Emc10, an inhibitor of neuronal maturation, represents the major transcriptional effect of the 22q11.2-associated microRNA dysregulation. Here, we demonstrate that mice in which the Df(16)A deficiency is combined with a LoF Mirta22 allele show rescue of key SCZ-related deficits, namely prepulse inhibition decrease, working memory impairment, and social memory deficits, as well as synaptic and structural plasticity abnormalities in the prefrontal cortex. Additional analysis of homozygous Mirta22 knockout mice, in which no alteration is observed in the above-mentioned SCZ-related phenotypes, highlights the deleterious effects of Mirta22 up-regulation. Our results support a causal link between dysregulation of a miRNA target and SCZ-related deficits and provide key insights into beneficial LoF mutations and potential new treatments.