Evaluation of the role of fatty acid-binding protein 7 in controlling schizophrenia-relevant phenotypes using newly established knockout mice
Evaluation of the role of fatty acid-binding protein 7 in controlling schizophrenia-relevant phenotypes using newly established knockout mice
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使用新建立的基因敲除小鼠评估脂肪酸结合蛋白7在控制精神分裂症相关表型中的作用
DOI：
10.1016/j.schres.2019.02.002
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发表时间：
2019
影响因子：
4.5
通讯作者：
Yoshikawa Takeo
中科院分区：
文献类型：
--
作者：
Shimamoto-Mitsuyama Chie;Ohnishi Tetsuo;Balan Shabeesh;Ohba Hisako;Watanabe Akiko;Maekawa Motoko;Hisano Yasuko;Iwayama Yoshimi;Owada Yuji;Yoshikawa Takeo
阻尼前脉冲抑制（PPI）是精神疾病（包括精神分裂症）中的一致观察结果，并有资格作为遗传评估的稳健内表型。利用高PPI的C57 BL/6 NCrlCrlj（B6 Nj）和低PPI的C3 H/HeNCrlCrlj（C3 HNj）近交系小鼠，我们在第10号染色体上发现了一个PPI的数量性状位点（QTL），并利用Fabp 7缺陷小鼠（B6. Cg-Fabp 7 KO）鉴定了Fabp 7作为PPI和精神分裂症发病机制的候选基因。在这里，考虑到残留的遗传物质从用于产生敲除（KO）小鼠的胚胎干细胞（ES）的可能性结转，我们着手重新解决在一个统一的遗传背景中的基因型-表型相关性。通过使用CRISPR-Cas9切口酶系统在C57 BL/6 NCrl（B6 N）背景中产生新的Fabp 7 KO小鼠模型，我们评估了Fabp 7消融对精神分裂症相关行为表型的影响。令我们惊讶的是，我们没有发现PPI或任何精神分裂症相关行为评分的显著差异，如在我们先前的B6. Cg-Fabp 7 KO小鼠中观察到的。我们确定了几个C3 H/He小鼠品系特异性等位基因的10号染色体QTL的间隔内，这是共享的129/Sv小鼠品系。这些来自129/Sv ES细胞的等位基因被保留在B6. Cg-Fabp 7 KO中，尽管多次回交，并且被认为是抑制PPI的原因。总之，我们的研究证明了在统一的B6 N背景下Fabp 7功能丧失的精确基因型-表型关系，并提出了进一步分析Fabp 7间隔侧翼基因组变异对表型影响的必要性。
Dampened prepulse inhibition (PPI) is a consistent observation in psychiatric disorders, including schizophrenia and qualifies as a robust endophenotype for genetic evaluation. Using high PPI C57BL/6NCrlCrlj (B6Nj) and low PPI C3H/HeNCrlCrlj (C3HNj) inbred mouse strains, we have previously reported a quantitative trait locus (QTL) for PPI at chromosome 10 and identifiedFabp7as a candidate gene for regulating PPI and schizophrenia pathogenesis usingFabp7-deficient mice (B6.Cg-Fabp7KO). Here, considering a possibility of carryover of residual genetic materials from embryonic stem (ES) cells used in generating knockout (KO) mice, we set out to re-address the genotype-phenotype correlation in a uniform genetic background. By generating a newFabp7KO mouse model in C57BL/6NCrl (B6N) background using the CRISPR-Cas9 nickase system, we evaluated the impact ofFabp7ablation on schizophrenia-related behavioral phenotypes. To our surprise, we found no significant differences in PPI or any of the schizophrenia-related behavioral scores, as observed in our previous B6.Cg-Fabp7KO mice. We identified several C3H/He mouse strain-specific alleles within the interval of chromosome 10-QTL, which are shared with 129/Sv mouse strains. These alleles, derived from 129/Sv ES cells, were retained in the B6.Cg-Fabp7KO, despite multiple backcrossing and are thought to be responsible for the dampened PPI. In summary, our study demonstrates a precise genotype-phenotype relation forFabp7loss-of-function in a uniform B6N background, and raises the necessity of further analysis of the effects of genomic variants flanking theFabp7interval on phenotypes.