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Production of Down syndrome model mice based on fine genetic information of human chromosome 21.

基于人类21号染色体精细遗传信息制作唐氏综合症模型小鼠。

基本信息

批准号：
16390307
负责人：
KUDOH Jun
金额：
$ 9.02万
依托单位：
KEIO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390307/
关键词：
Down syndrome human chromosome 21 disease model mice HAC mouse chromosome 17 mouse chromosome 10 BAC trisomy 21 マウス16番染色体

项目摘要

Down syndrome (DS), or trisomy 21, is caused by the inheritance of three instead of two copies of human chromosome 21 (HC21). It is difficult to identify critical gene(s) for each phenotype because the number of patients with partial trisomy 21 is limited and the phenotype is highly variable in patients with even full trisomy 21. Therefore, mouse models for DS have been generated and used to study phenotype-genotype correlations. We have analyzed transcripts, structure and function of genes on human chromosome 21q22.3. Based on the information, we focus on genes in the regions homologous to mouse chromosomes 10 and 17 to generate novel mouse models for DS. BAC clones containing the entire target gene(s) were selected and transferred into mouse embryonic stem (ES) cells using a human artificial chromosome (HAC) as a vector in collaboration with Dr.Tuneko Okazaki and her colleagues at Fujita Health University. Using these HAC-containing ES cells, we have generated chimeric mice harboring a HAC that carries human chromosome 21 gene(s). Subsequent genetic crossing showed that HAC was stably transmitted to progeny. RT-PCR analysis of three human genes (CBS, U2AF1, CRYAA) on HAC in various tissues of "transminicromosomal (TMC)" mice harboring a HAC revealed that the expression pattern of human genes in mouse tissues is similar to that in human tissues. However, expression level of human CBS gene in various mouse tissues was less than 5% of endogenous mouse counterpart. We speculated that the reduced expression level of human gene was due to species specificities of mouse transcription factors.

唐氏综合症 (DS) 或 21 三体症是由人类 21 号染色体 (HC21) 的三个而不是两个拷贝的遗传引起的。由于部分 21 三体性患者的数量有限，而且即使是完全 21 三体性患者的表型也有很大差异，因此很难确定每种表型的关键基因。因此，已生成 DS 小鼠模型并用于研究表型-基因型相关性。我们分析了人类染色体 21q22.3 上基因的转录本、结构和功能。根据这些信息，我们重点关注与小鼠 10 号和 17 号染色体同源区域的基因，以生成新的 DS 小鼠模型。与藤田健康大学的 Tuneko Okazaki 博士及其同事合作，选择包含完整靶基因的 BAC 克隆，并使用人类人工染色体 (HAC) 作为载体将其转移到小鼠胚胎干 (ES) 细胞中。利用这些含有 HAC 的 ES 细胞，我们培育出了含有 HAC 的嵌合小鼠，该 HAC 携带人类 21 号染色体基因。随后的遗传杂交表明HAC可以稳定地遗传给后代。对携带 HAC 的“跨小染色体（TMC）”小鼠不同组织中 HAC 上的三个人类基因（CBS、U2AF1、CRYAA）进行 RT-PCR 分析，结果表明人类基因在小鼠组织中的表达模式与人类组织中的表达模式相似。然而，人CBS基因在小鼠各组织中的表达水平低于内源性小鼠对应物的5%。我们推测人类基因表达水平的降低是由于小鼠转录因子的物种特异性造成的。