Cell-cycle control of cell polarity in epidermal patterning and differentiation

表皮图案形成和分化中细胞极性的细胞周期控制

• 批准号: 9923446
• 负责人: Danelle N Devenport
• 金额: $ 34.67万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-05 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923446
• 关键词: Address; Affect; Architecture; Behavior; Biochemical; Biological Assay; Biological Models; Biological Process; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Polarity; Cell division; Cells; Cellular biology; Chemicals; Congenital Heart Defects; Cystic Kidney Diseases; Cytokinesis; Data; Defect; Development; Disease; Endosomes; Ensure; Epidermis; Epithelial; Epithelium; Event; Genes; Growth; Hair follicle structure; Homeostasis; Image; Imaging technology; Impairment; Interphase; Knowledge; Labyrinth; Light; Link; Maintenance; Malignant Neoplasms; Mammalian Genetics; Mediating; Membrane; Mitosis; Mitotic; Molecular; Natural regeneration; Neoplasm Metastasis; Neural Tube Defects; Pattern; Phosphotransferases; Process; Prophase; Proteins; Proteomics; Regulation; Role; Site-Directed Mutagenesis; Skin; Spatial Distribution; Stratification; Subcellular structure; Time; Tissue Preservation; Tissues; Tumor Suppression; Vesicle; daughter cell; ex vivo imaging; experimental study; mutant; novel; planar cell polarity; polo-like kinase kinase 1; preservation; progenitor; public health relevance; restoration; skin organogenesis; stem cell proliferation; targeted treatment; tumor

 DESCRIPTION (provided by applicant): Loss of cell polarity and invasive behavior are regarded as hallmarks of cancer, but surprisingly little is known about the mechanisms that preserve cell polarity during tissue growth and turnover. Polarity refers to the asymmetric partitioning of membrane components and subcellular structures, is oriented along both apicobasal and planar axes, and is essential for the proper assembly and function of epithelial tissues. The preservation of cell polarity is of crucial importance in tumor suppression and therefore, special mechanisms must exist to preserve polarity when cells divide. Consistent with this notion, we previously discovered a novel and unexpected mechanism that preserves planar polarity in dividing cells of the skin epidermis. More recent data demonstrate this mechanism is controlled directly by mitotic kinases, the same machinery that controls cell cycle progression and is deregulated in cancer. This is the first demonstration that cell division and planar cell polarity are controlled by the same regulatory machinery, and may explain why, in cancer, hyperproliferation and cellular disorder are so closely intertwined. We hypothesize that the cell cycle machinery regulates cell polarity to ensure its preservation when cells divide, and that aberrations uncoupling polarity from cell cycle control will impair tissue architecture and proliferative homeostasis. Using a multifaceted approach combining mammalian genetics with cell biology, proteomics, and time-lapse imaging we will address our hypothesis in the context of epidermal development and regeneration. Specifically we will 1) define the cell cycle- dependent events that regulate planar cell polarity throughout mitotic progression; 2) determine how the landscape of proliferation across the epidermis impacts global planar cell polarity, and 3) decipher how perturbations in planar cell polarity influence proliferation and differentiation durig skin development and homeostasis. Successful completion of the proposed experiments will bring a shift in our understanding of how tissue architecture and growth are connected where it is recognized that proliferation and cell polarity are connected by the same machinery. Understanding the mechanisms that mediate crosstalk between these two essential cell biological processes will help us to reevaluate current therapies that target cell cycle machinery in light of their effects on cell and tissue polarity.

 描述（由申请人提供）：细胞极性丧失和侵袭行为被认为是癌症的标志，但令人惊讶的是，对组织生长和周转期间保持细胞极性的机制知之甚少。极性是指膜成分和亚细胞结构的不对称分配，沿顶基轴和平面轴沿着，对上皮组织的正确组装和功能至关重要。细胞极性的保持在肿瘤抑制中至关重要，因此，必须存在特殊的机制来保持细胞分裂时的极性。与这一概念相一致，我们以前发现了一种新的和意想不到的机制，在皮肤表皮的分裂细胞中保持平面极性。最近的数据表明，这种机制直接由有丝分裂激酶控制，有丝分裂激酶是控制细胞周期进程的同一种机制，在癌症中失调。这是第一次证明细胞分裂和平面细胞极性是由相同的调节机制控制的，并且可以解释为什么在癌症中，过度增殖和细胞紊乱如此紧密地交织在一起。 我们假设，细胞周期机制调节细胞极性，以确保其保存细胞分裂时，和畸变解耦极性从细胞周期控制将损害组织结构和增殖稳态。使用多方面的方法相结合的哺乳动物遗传学与细胞生物学，蛋白质组学和延时成像，我们将解决我们的假设在表皮发育和再生的背景下。具体而言，我们将1）定义在整个有丝分裂进程中调节平面细胞极性的细胞周期依赖性事件; 2）确定跨表皮的增殖景观如何影响整体平面细胞极性，以及3）破译平面细胞极性的扰动如何影响皮肤发育和稳态期间的增殖和分化。 成功完成拟议的实验将使我们对组织结构和生长如何联系的理解发生转变，人们认识到增殖和细胞极性是由相同的机制联系在一起的。了解介导这两个基本细胞生物学过程之间串扰的机制将有助于我们重新评估目前针对细胞周期机制的治疗方法，这些治疗方法对细胞和组织极性的影响。