Creation and analysis of animal model monitoring abnormal cell replication

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DNA mismatch repair is a well-known system managing and controlling genomic structure that is conserved widely from bacteria to humans, and its mechanism is an action to substitute the gap of the genomic sequence into an accurate structure by the polymerase possessing proofreading activity. We found previously a unique phenotype in MRL mouse testis, i.e. metaphase-specific apoptosis (Msa). In addition, as a result of a genetics analysis of the testis, we found the mutation of Exonuclease 1(Exo1) as a factor associated with Msa. The purpose of this research project is to create and analyze the abnormal model mouse for the cell replication monitoring system paying attention to MRL mouse strain.In this research, we firstly clarified several unique phenotypes in MRL mice, i.e. the existence of heat stress resistant spermatocytes, the appearance of oocytes in the testis and the development of rete ovarii-derived ovarian cysts. Secondarily, the congenic mice carrying telomere region of the chromosome 1 in MRL mice were created and analyzed to confirm the re-appearance of Msa and autoimmune disease. Next, transgenic mice were created by introduction of antisense Exo1 and truncated Exo1 to examine whether the abnormality in the testis was derived from its volume or truncation. Finally, the exon skipping of Exo1 gene was examined in vitro, and the localization of Exo1 in the testis was clarified by immunohistochemistry using a specific antibody originally produced in the present study.These investigations suggest that many phenotypes presented in MRL mice are due to the abnormal activity monitoring cell replication, however, it is revealed that other factors independent on that might effect on some phenotypes in MRL mice. It would be further expected to use MRL mice as several unique models as well as an autoimmune disease.