The establishment of an in vivo system estimating the significance of a responsible gene for murine polygenic dianase model by using ES lines derived thorn the disease model

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In polygenic disorders, the identification of a responsible gene is not only difficult but experimental systems to demonstrate the significance of the candidate gene in vivo has not yet been well established. In this report, we tried to identify a responsible gene with a polymorphism and to establish ES lines from polygenic mouse disease model to generate a mouse with the genes of normal alleles. To achieve this goal, two models were utilized: autoimmune dermatitis in MRL lpr mice and autoimmune diseases after thymectomized BALB/c but not C57BL/6 mice.1) Autoimmune dermatitis in MRL lpr miceWe paid attention to the different frequency of autoimmune dermatitis between MRL lpr (FAS receptor deficient) and MRL gld (its ligand deficiency) mice. Genes from C3H mice as MRL gld mice were generated were hypothesized to be responsible for the frequency. The region of C3H mice in MRL gld mice was determined between 38.1 and 102 cM in mouse chromosome 1. Because of the region, it was found that MRL gld mice should be backcrossed more generations to discover' responsible genes. On the other hand, ES cell lines were generated from MRL lpr mice. These cells expressed differential markers consistent with undifferentiated state and retained capability of generating chimeric mice after blastcyst injection but not of differentiating into germ cells.2) Autoimmune diseases in thymectomized BALB/c miceTo identify a responsible gene for different frequency of autoimmune diseases between thymectomized BALB/c and C57BL/6 mice, regulator genes for regulatory T cells were hypothesized to be involved. We found a gene with polymorphism in mouse chromosome 2 and generated a congenic BALB/c mice with the gene of C57BL/c mice and a congenic C57BL/c mice with the gene of BALB/c mice. These mice were expanded in number to examine the significance of the gene in the different frequency of autoimmune diseases.