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Analysis of physiological role of transcriptional regulators using gene knock out mice

利用基因敲除小鼠分析转录调节因子的生理作用

基本信息

批准号：
06454172
负责人：
ISHII Shunsuke
金额：
$ 4.48万
依托单位：
The Institute of Physical & Chemical Research (RIKEN)
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06454172/
关键词：
transcription factors mutant mice physiological function 変異マウス

项目摘要

In this research, the mutant mice lacking the gene encoding various CRE (cAMP response element)-binding proteins described below were made and the observed abnormalities were analyzed from various aspects.So far, more than 10 CRE-binding proteins were identified by cDNA cloning. These proteins can be divided into two types ; one is CREB type which is directly phosphorylated by PKA,and another is CRE-BP1 (also called ATF-2) which is phosphorylated with Jun kinase of the stress-activated kinases. Since CRE-BP1 forms a heterodimer with c-Jun, it is important for a cross-talk between PKA and PKC pathways. CRE-BP1 family contains other two members, CRE-BPa and ATF-a. We have made three kinds of mutant mice lacking CRE-BP1, CRE-BPa, or ATF-a genes using the gene knock out technique. All of heterozygotes appears to be normal, but the abnormalities were observed in all of the homozygotes. The CRE-BP1 deficient homozygotes died within 20-30 min after birth. No obvious histological abnormalities were found in all tissues, suggesting that an abnormal signal transduction in the neuronal cells is caused by deficiency of CRE-BP1 activity which destroys the noram function of central nervous system. The CRE-BPa-deficient homozygotes are embryonic lethal. The ATF-a deficiency appears to cause the male-specific embryonic lethality. These results indicate that each of three members of the CRE-BP1 gene family have their own physiological role.

本研究制作了编码下述各种CRE（cAMP反应元件）结合蛋白的基因缺失的突变小鼠，从多个方面分析了观察到的异常，通过cDNA克隆鉴定了10种以上的CRE结合蛋白。这些蛋白质可分为两种类型;一种是CREB型，其被PKA直接磷酸化，另一种是CRE-BP 1（也称为ATF-2），其被应激激活激酶中的Jun激酶磷酸化。由于CRE-BP 1与c-Jun形成异源二聚体，因此对于PKA和PKC途径之间的串扰很重要。CRE-BP 1家族包括CRE-BPa和ATF-a两个成员。我们利用基因敲除技术制备了三种缺失CRE-BP 1、CRE-BPa和ATF-a基因的突变小鼠。所有杂合子均表现正常，而所有纯合子均出现异常。CRE-BP 1缺陷纯合子在出生后20-30分钟内死亡。所有组织中均未发现明显的组织学异常，提示CRE-BP 1活性缺乏导致神经细胞内信号传导异常，破坏了中枢神经系统的noram功能。CRE-BPa-缺陷纯合子是胚胎致死的。ATF-a缺陷似乎导致雄性特异性胚胎致死。这些结果表明，CRE-BP 1基因家族的三个成员中的每一个都有自己的生理作用。