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Cloning of left-right determining (inv) gene

左右决定（inv）基因的克隆

基本信息

批准号：
08670039
负责人：
YOKOYAMA Takahiko
金额：
$ 1.47万
依托单位：
Tokyo Women's Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670039/
关键词：
asymmetry sirus inversus mutant inv ankyrin gene YAC トランスジェニックマウス

项目摘要

Almost all internal organs of vertebrate body have distinctive left-right asymmetry. The inv mutation was found in a family of transgenic mice in which tyrosinase minigene was introduced. Homozygous inv mice show a consistent reversal of left/right polarity, in contrast to randomization of the left-right asymmetry reported in other genetic and experimentally induced situs inversus mutants. Since no other tyrosinase transgenic families of mice show any abnormalities of the left-right asymmetry, the inv mutant is considered to be caused by insertional mutation and the transgenic integration destroyed an essential gene or genes to establish handed asymmetry. We cloned a candidate gene, which is responsible for reversal of left-right asymmetry in the inv mutation.The deduced amino acid sequence of the candidate gene encodes 1062 amino acids and has 15 consecutive repeats of Ank/swi6 motif in its N-terminal half. The gene starts expressing as early as embryonic day 7 in mice and that kidney and liver show the highest level of expression among tissues in adult mice. Ank/swi6 motif is implicated to bind proteins. We assume that the inv gene product creates asymmetric distribution of intracellular molecules by binding other proteins with its Ank/swi6 motif, then establishes cell polarity and that this cell polarity induces downstream cascade like asymmetric expression of cell signaling molecules and receptor.

几乎所有脊椎动物的内脏器官都具有明显的左右不对称性。在一个转酪氨酸酶小基因小鼠家系中发现inv突变。纯合子inv小鼠显示出一致的左/右极性逆转，与其他遗传和实验诱导的原位反转突变体中报道的左右不对称的随机化相反。由于没有其他酪氨酸酶转基因小鼠家族显示任何左右不对称的异常，因此inv突变体被认为是由插入突变引起的，并且转基因整合破坏了建立手性不对称的一个或多个必需基因。我们克隆了一个逆转inv突变中左右不对称性的候选基因，该基因编码1062个氨基酸，N端有15个Ank/swi 6基序重复序列。该基因早在小鼠胚胎第7天就开始表达，肾脏和肝脏在成年小鼠的组织中表达水平最高。Ank/swi 6基序与蛋白质结合有关。我们假设inv基因产物通过与其Ank/swi 6基序结合其他蛋白质而产生细胞内分子的不对称分布，然后建立细胞极性，并且这种细胞极性诱导下游级联反应，如细胞信号分子和受体的不对称表达。