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