Introduction of a de novo Creb-binding protein gene mutation in sperm to produce a Rubinstein-Taybi syndrome model using inbred C57BL/6 mice
Introduction of a de novo Creb-binding protein gene mutation in sperm to produce a Rubinstein-Taybi syndrome model using inbred C57BL/6 mice
复制标题
在精子中引入新的 Creb 结合蛋白基因突变，使用近交 C57BL/6 小鼠产生 Rubinstein-Taybi 综合征模型
DOI：
10.1016/j.brainres.2020.147140
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发表时间：
2020
期刊：
影响因子：
2.9
通讯作者：
S Ishii
中科院分区：
文献类型：
--
作者：
T.Takagi;Y Higashi;M Asai;S Ishii
神经发育障碍，包括智力残疾和自闭症谱系障碍，通常是由新常染色体显性突变引起的。虽然小鼠模型经常被用来研究这些疾病，但遗传背景有时会影响突变表型的出现或严重程度。在之前的一份报告中，我们开发了一种系统，使用Cre-loxP系统来产生新的杂合突变小鼠，而不需要维护杂合突变系本身(Takagi等人。2015年)。为了进一步验证Thede novomomation系统在精子中的适用性，我们使用该系统制作了Rubinstein-Taybi综合征的小鼠模型，使用了一个Cbphoneogig突变体，据报道，这种突变体在C57BL/6背景下很难维持。在这里，我们发现了具有C57BL/6背景的CBP功能丧失杂合突变小鼠，在旷场试验中表现出明显的头面部表型和运动能力降低，这在混合遗传背景Cbpheter突变系小鼠的功能丧失中没有观察到，但在具有混合遗传背景的显性阴性Cbpheter合子突变系小鼠中观察到。与此同时，新杂合子Cbp突变小鼠的存活率仍然表现出很大的变异性，尽管它们有近亲繁殖的背景。这些结果进一步证实了生殖细胞中使用的新克隆系统对于稳定生产和分析常染色体显性遗传病小鼠模型是有效的，而常染色体显性遗传病小鼠模型通常很难作为突变小鼠系维持下去。
Neurodevelopmental disorders, including intellectual disability and autism spectrum disorder, are often caused byde novoautosomal dominant mutations. While mouse models are frequently used to investigate these disorders, the genetic background sometimes affects the appearance or severity of mutant phenotypes. In a previous report, we developed a system to producede novoheterozygous mutant mice using the Cre-LoxP system without the need to maintain the heterozygous mutant line itself (Takagi et al. 2015). To further verify the applicability of thede novomutation system in sperm, we used this system to produce a mouse model for Rubinstein-Taybi syndrome, using aCbpheterozygous mutant, which has been reported to be difficult to maintain on a C57BL/6 background. Here, we show thatde novo Cbp- loss-of-function heterozygous mutant mice with a C57BL/6 background, present with a clear craniofacial phenotype and reduced locomotor activity in the open field test, which was not observed in the loss-of-function ofCbpheterozygous mutant line mice with a mixed genetic background, but was observed in the dominant negativeCbpheterozygous mutant line with a mixed genetic background. Meanwhile, thede novoheterozygousCbpmutant mice still showed great variability in survival rates despite their inbred background. These results further confirmed that thede novomutation system used in germ cells is effective for stable production and analysis of an autosomal dominant disorder mouse model, which is often difficult to maintain as a mutant mouse line.