@misc{oai:ir.soken.ac.jp:00001002, author = {田中, 成和 and タナカ, シゲカズ and TANAKA, Shigekazu}, month = {2016-02-17, 2016-02-17}, note = {Two dominant mouse skin mutants, Recombinant-induced mutation 3 (Rim3) and Rex denuded (Re^den), 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.
　　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.
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^-) 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^- genetic background.
To do this, I generated mice heterozygous for both of the Rim3 and Trp53^- alleles. As a result, the double heterozygous mice (GsdmA-3^Rim3/+; Trp53⁺/+) 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., application/pdf, 総研大甲第808号}, title = {Functional analysis of Rim3 mutation that exhibits aberrant epidermal morphogenesis.}, year = {} }