Cross-talk Between Desmosomal Proteins and Signaling Pathways in the Skin

描述（由申请人提供）：桥粒是高度动态的细胞-细胞粘附复合物，具有调节其粘附特性和分子组成的能力，从而影响细胞迁移、细胞分选和细胞分化。实现这一点的一种机制是改变组装到桥粒中的桥粒钙粘蛋白[桥粒柯林斯（Dsc）和桥粒芯糖蛋白（Dsg）]的比例。在皮肤和皮肤附件发育过程中，对控制桥粒功能的基因调控途径知之甚少。本申请的目的是确定在皮肤附属物（例如毛囊、乳腺）发育期间如何调节Dsc基因的表达。我们已经从Wnt、NFkB和Notch信号通路中鉴定出差异调节培养细胞中Dsc基因的转录因子。为了验证我们的假设，即这些转录因子也控制培养的角质形成细胞和发育中的皮肤附件中的Dsc基因表达，我们提出了以下具体目标：1.分析主要信号转导途径对桥粒柯林斯蛋白表达的影响。2.）研究Wnt信号通路对发育过程中Dsc 2和Dsc 3基因表达的影响。3.）第三章使用体内互补测定来确定体内Dsc 3功能是否需要Wnt信号传导。该项目的结果将导致更好地了解形态发生过程，如附属物的形成，在发展过程中受到监管。此外，了解桥粒基因的调控将有助于开发新的概念，在治疗桥粒功能受损引起的获得性和遗传性疾病。项目叙述：该项目的目标是确定在哺乳动物发育过程中控制桥粒功能的基因调控途径，特别是控制皮肤及其附属物（例如毛囊，乳腺）形成的途径。

DESCRIPTION (provided by applicant): Desmosomes are highly dynamic cell-cell adhesion complexes that have the ability to adjust their adhesive properties and molecular composition, thereby affecting cell migration, cell sorting and cell differentiation. One mechanism by which this is achieved is a change in the ratio of desmosomal cadherins [desmocollins (Dsc) and desmogleins (Dsg)] that are assembled into the desmosome. Very little is known about the gene regulatory pathways that control desmosome function during skin and skin appendage development. The goal of the present application is to determine how the expression of the Dsc genes is regulated during skin appendage (e.g. hair follicles, mammary gland) development. We have already identified transcription factors from the Wnt, NFkB and Notch signaling pathways that differentially regulate Dsc genes in cultured cells. To test our hypothesis that these transcription factors also control Dsc gene expression in cultured keratinocytes and in developing skin appendages, we propose the following specific aims: 1.) To analyze the effects of major signal transduction pathways on the expression of desmocollins in vitro. 2.) To determine the effects of Wnt Signaling on Dsc2 and Dsc3 gene expression during development. 3.) To use an in vivo complementation assay to determine whether Wnt signaling is required for Dsc3 function in vivo. The results of this project will lead to a better understanding of how morphogenetic processes, such as appendage formation, are regulated during development. Furthermore, understanding the regulation of desmosomal genes will help to develop new concepts in the therapy of acquired and inherited diseases caused by impaired desmosome function. Project Narrative: The goal of this project is to identify gene regulatory pathways that control desmosome function during mammalian development, in particular pathways that control the formation of the skin and its appendages (e.g. hair follicles, mammary glands).