Severe Fanconi Anemia phenotypes in Fancd2 depletion mice
Severe Fanconi Anemia phenotypes in Fancd2 depletion mice
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Fancd2 缺失小鼠的严重范可尼贫血表型
DOI：
10.1016/j.bbrc.2019.04.201
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发表时间：
2019
影响因子：
3.1
通讯作者：
Zhang Tingting
中科院分区：
文献类型：
--
作者：
Yang Qiao;Xie Hui;Zhong Yixinhe;Li Dongbo;Ke Xianfu;Ying Huazhong;Yu Bing;Zhang Tingting
范可尼贫血（FA）是一种遗传性疾病，其特征是先天性功能障碍、骨髓衰竭和对DNA损伤的超敏反应。FANCD 2蛋白在FA通路中起着重要作用。为了研究FANCD 2在体内的作用，我们在同源C57 BL/6 J背景下使用Crispr-Cas9产生并表征了Fancd 2基因5'端缺失7 bp的新的Fancd 2敲除小鼠品系。与先前的ES细胞靶向Fancd 2模型相比，Fancd 2 −/−小鼠表现出相似但总体上更严重的表现。这些特征包括胚胎和出生后致死率增加，小眼症的发生率较高，更严重的性腺功能减退。我们在Fancd 2 −/−小鼠中观察到的贫血在其他FA模型中没有描述。进一步的研究表明，Fancd 2 −/−骨髓前体细胞凋亡增加，G2/M期阻滞，对MMC敏感，IR损伤。总的来说，Fancd 2 −/−小鼠与FA患者症状的相似性更高，这将有助于了解FA中全血细胞减少和骨髓衰竭的孤雌生殖。
Fanconi anemia (FA) is a genetic disorder characterized by congenital malfunction, bone marrow failure and hypersensitivity to DNA damage. FANCD2 protein play the central role in FA pathway. To study the in vivo role of FANCD2, we generated and characterized a newFancd2knockout mouse strain with 7bp deletion inFancd2gene 5’ terminus using Crispr-Cas9 in congenic C57BL/6J background. ThisFancd2−/−mice displayed similar but overall more severe manifestation than the previous ES cell targetedFancd2model. These features include increased embryonic and postnatal lethality rate, higher incidence of microphthalmia, and more severe hypogonadism. The anemia we observed in thisFancd2−/−mice has not been described in other FA models. Further study indicated that the hematopoiesis deficiency was associated with increased apoptotic cell death, G2/M phase arrest and hypersensitivity to MMC and IR damage ofFancd2−/−bone marrow progenitor cells. Collectively, the resultingFancd2−/−mice with higher resemblance of FA patient symptoms, will be useful in understand the parthenogenesis of pancytopenia and bone marrow failure in FA.