Functional analysis of Rim3 mutation that exhibits aberrant epidermal, morphogenesis Functional analysis of Rim3 mutation that exhibits aberrant epidermal morphogenesis.

博士論文

Two dominant mouse skin mutants, Recombinant-induced mutation 3 (Rim3) and Rex denuded (Re<SUP>den</SUP>), arose spontaneously in different inbred strains, but exhibit very similar phenotype of hyperkeratosis and alopecia. Both mutants have a genetic alteration in GasderminA-3 (GsdmA-3), which is a member of novel gene family, Gsdm. The Gsdm family commonly share unique leucine-rich C-terminus domain, but the functions of GsdmA-3 and Gsdm family are largely unknown.<br />　　In this study, to elucidate the function of GsdmA-3 in the epidermal morphogenesis, I conducted analysis of spatiotemporal expression patterns of GsdmA-3 and the related genes. In addition, I carried out in-depth characterization of the Rim3 phenotype. The results indicated that GsdmA-3 is specifically expressed in differentiated keratinocytes in epidermis after postnatal stage, but not in proliferating epidermal cells. Immunohistochemical analysis of BrdU-labeled epidermis revealed hyperproliferation and misdifferentiation of the upper follicular cells and the epidermis in the Rim3 mutant. All the results suggested that GsdmA-3 is involved in downregulation of cellproliferation and differentiation of the epidermal stem cells.<br />As collaboration with a research group of National Cancer Institute, Tokyo, it was demonstrated that a human homologue GSDMA has a tumor suppressor activity. Mice heterozygous for Trp53 knockout (Trp53<SUP>-</SUP>) allele are known to frequently develop lymphomas, but never develop skin tumors. Although mice heterozygous for the Rim3 mutation alone develop no skin tumors, I examined whether GsdmA-3 is involved in tumor suppression in the Trp53<SUP>-</SUP> genetic background.<br />To do this, I generated mice heterozygous for both of the Rim3 and Trp53<SUP>-</SUP> alleles. As a result, the double heterozygous mice (GsdmA-3<SUP>Rim3</SUP>/+; Trp53<SUP>+</SUP>/+) developed multiple metastatic squamous cell carcinomas (SCC) as early as 7 months of the age. In conjunction with the data that a human homologue GSDMA is a tumor suppressor for gastric cancer in human, this result suggested that GsdmA-3 has a function to prevent tumor development in the mouse skin as well.

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総研大甲第808号