| Research Abstract |
Stress-activated protein kinase/c-Jun NH_2-terminal kinase (SAPK/JNK) is activated by many types of cellular stresses and extracellular signals. Recent studies, including the analysis with knockout mice, have led to progress towards understanding the physiological roles of SAPK/JNK activation in embryonic development in addition to immune responses. SAPK/JNK activation plays essential roles in organ formation during mouse development by regulating cell survival, apoptosis, and proliferation. Two SAPK/JNK activators, SEK1 and MKK7, are required for fetal liver formation and full activation of SAPK/JNK, which responds to various stimuli in an all-or-none manner. Thus, several genes that are crucial for liver formation and function have been isolated in mice and confirmed by reverse genetics. Although a reverse genetic approach is powerful in characterizing function of known genes, knowledge of genes in liver formation and disease is still limited. Therefore, identifying mutations affecti
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ng these aspects will uncover genes required for these processes. Systematic forward genetic screens for mutations affecting liver formation and function such as hepatic bud formation, liver morphogenesis, bile color in the gall bladder, lipid metabolism, and liver laterality have been carried out in Medaka, Oryzias latipes. To isolate mutants that model human liver diseases, we are analyzing these mutations. Among them, kendama (ken) mutation was isolated as a gene that affects the laterality of the liver. ken mutant was viable and fertile with inverted positions of liver and heart, and with inverted spiral of gut. Interestingly, the spleen was almost lost in ken mutant. This phenotype is very similar to human genetic disease 'asplenia' whose gene mutation is still unknown. Furthermore, white livers consisting of bloated and Oil red O-positive hepatocytes were observed in ken mutants. Thus, ken mutation models human disease asplenia and Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). Especially, NAFLD and NASH are serious human diseases in the modern world, so ken mutation may shed a new light on the molecular mechanisms of these diseases and the preventive medicine. Less
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