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

描述(申请人提供)：桥粒是高度动态的细胞-细胞黏附复合体，具有调节其黏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。实现这一点的一个机制是改变桥粒钙粘附素[桥粒粘附素(DSC)和桥粒糖蛋白(DSG)]的比率，这些桥粒钙粘附素组装成桥粒。在皮肤和皮肤附属物发育过程中，控制桥粒功能的基因调控途径知之甚少。本应用的目的是确定DSC基因在皮肤附属物(如毛囊、乳腺)发育过程中的表达是如何调节的。我们已经从Wnt、NFkB和Notch信号通路中确定了转录因子，这些信号通路对培养细胞中的DSC基因进行了差异调控。为了验证我们的假设，即这些转录因子也控制着培养的角质形成细胞和发育中的皮肤附件中DSC基因的表达，我们提出了以下具体目标：1)分析主要信号转导通路在体外对桥粒基质蛋白表达的影响。2.)探讨Wnt信号在发育过程中对Dsc2和Dsc3基因表达的影响。3.)用体内互补实验来确定Dsc3在体内的功能是否需要Wnt信号。该项目的结果将有助于更好地理解形态发生过程，如附肢形成，是如何在发育过程中调节的。此外，了解桥粒基因的调控将有助于在桥粒功能受损引起的获得性和遗传性疾病的治疗中发展新的概念。项目简介：本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件(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).