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内容記述 |
<i>Gsdm/GSDM</i> is a novel gene family consisting of structurally-related seven mouse genes and four human genes. A member of this family，<i>Gsdma3</i>，is known to be the causative gene of a mouse skin mutant <i>Rim3</i>，which exhibits epidermal hyperplasia，hyperkeratosis and abnormal hair development. All members of the <i>Gsdm/GSDM</i> family are expressed predominantly in epithelial cells of various different tissues including skin and gastrointestinal tract. Thus far，expression patterns of <i>Gsdma genes</i> clustering in the mouse chromosome 11 have been well analyzed，and it is revealed that they are expressed in skin and upper gastrointestinal tracts，such as esophagus and stomach，in a tissue specific manner. The phenotypes of <i>Rim3</i> and other mutants of <i>Gsdma3</i> have been well characterized．The results of these studies suggested that function of the <i>Gsdm/GSDM</i> gene family is involved in regulation of proliferation and differentiation of epithelial cells. <br /> In mouse，other members of the <i>Gsdm/GSDM</i> family，<i>Gsdmc</i> and <i>Gsdmd</i>，are known to be expressed in intestinal tracts, small intestine and colon, but information about their genome structures and fine expression patterns is very limited. Moreover, functional analysis of the <i>Gsdmc</i> and <i>Gsdmc</i> genes has been hampered by absence of available mutants.<br /> In this study, first I carried our molecular cloning of a new <i>Gsdmc</i>-related gene, and analyzed fine genome structures of the <i>Gsdmc</i>and <i>Gsdmd</i> genes primarily by intensive search for public genome databases. As a consequence, I found that four <i>Gsdmc</i>genes are clustering in the mouse chromosome 15, and <i>Gsdmd</i> is linkcd to the <i>Gsdmc</i> cluster. Second, I conducted extensive analysis of expression profiling of the <i>Gsdmc</i>and <i>Gsdmd</i>genes by Northern blot, quantitative PCR and <i>in situ</i> hybridization. The results clearly showed that the expression patterns of these genes are highly tissue specific. Moreover，Position restricted expression of each gene is observed . It was also notable that all genes are expressed in differentiated cells but not in proliferating cells and stem cells, as is the case with the <i>Gsdma</i>cluster genes. <br /> Finally, I generated <i>Gsdmd</i>-null mutant mice to elucidate function of this gene. Surprisingly, the mutant mice showed no marked phenotype in the external appearance, histology of the small intestine and the colon, and cell differentiation and proliferation in the intestinal tract. However, I found that mortality of the mutant homozygotes is elevated after 5 months of age. Furthermore, mutant mice exposed to γ-irradiation revealed to have defect in cell proliferation and tissue recovering in the intestinal tract after injury. This result demonstrated that <i>Gsdmd</i>plays a role in homeostasis rather than development and morphogenesis of intestinal tract. All results of the study showed that functions of the members of the <i>Gsdm</i> family are not simple, but might be rather diverse depending on tissues. Taking account of the strictly restricted and differential expression patterns of each member of the <i>Gsdm</i>gene family, may play differential functions depending on tissues that express specific member(s) of the <i>Gsdm</i> gene family. |
要旨・審査要旨 (233.1 kB)
