Desmocollin 3 in the development and maintenance tissues

描述（由申请人提供）： 桥粒是连接上皮细胞的细胞连接点。这些连接的缺陷会导致皮肤、其附属物和心脏的获得性和遗传性疾病。细胞培养实验证明桥粒的跨膜成分桥粒柯林斯（dsc）对细胞粘附和桥粒与上皮细胞中间丝细胞骨架的连接至关重要。这个应用程序的重点是dsc 3，我们已经证明，这是所需的正常胚胎发育的小鼠。 体外实验表明，dsc 3在外胚层来源的组织和器官的发育和分化中起着重要作用，很可能是通过提供来自相同分化途径的细胞之间的选择性粘附。此外，越来越多的证据表明dsc 3在某些癌症中可能起肿瘤抑制作用。为了明确dsc 3在体内的作用，我们提出了以下具体目标：1。通过对dsc 3基因敲除小鼠的分析，阐明dsc 3在早期胚胎发育中的作用。2.通过在胚胎和出生后发育的不同时间点消除条件性dsc 3基因敲除小鼠的dsc 3表达来确定dsc 3对皮肤发育和维持的贡献。我们将采用基于Cre/LoxP的基因敲除系统，该系统允许系统性和局灶性基因消融。3.通过分析dsc 3缺失的角质形成细胞来表征dsc 3去除对体外桥粒组装和功能的影响。4.通过在肿瘤从良性乳头状瘤转化为浸润性癌的不同阶段失活dsc 3基因，确定dsc 3基因消融是否促进皮肤癌发生方案小鼠的肿瘤进展。

DESCRIPTION (provided by applicant): Desmosomes are cell junctions that connect epithelial cells. Defects in these junctions cause acquired and inherited diseases of the skin, its appendages and the heart. Cell culture experiments provided evidence that desmocollins (dsc), which are transmembrane components of desmosomes, are crucial for cell adhesion and the connection of desmosomes to the intermediate filament cytoskeleton of epithelial cells. This application focuses on dsc3, which we have shown to be required for normal embryonic development in the mouse. In vitro experiments suggest that dsc3 plays an important role in the development and differentiation of ectoderm-derived tissues and organs, most likely by providing selective adhesion between cells from the same differentiation pathway. Furthermore, evidence is accumulating that dsc3 might function as tumor suppressor in certain carcinomas. To define the role of dsc3 in vivo, we propose the following specific aims: 1. To elucidate the role of dsc3 in early embryonic development by analyzing dsc3 knockout mice that we have generated. 2. To determine the contributions of dsc3 to development and maintenance of the skin by ablating dsc3 expression in conditional dsc3 null mice at different time points during embryonic and postnatal development. We will employ a Cre/LoxP-based gene knockout system that allows systemic and focal gene ablation. 3. To characterize the effects of dsc3 ablation on desmosome assembly and function in-vitro by analyzing dsc3 null keratinocytes. 4. To determine whether dsc3 gene ablation facilitates tumor progression in mice subjected to a skin carcinogenesis protocol by inactivating the dsc3 gene at different stages of tumor conversion from benign papillomas to invasive carcinomas.