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

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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.