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）：细胞极性的丧失和侵袭行为被认为是癌症的标志，但令人惊讶的是，人们对组织生长和周转过程中保持细胞极性的机制知之甚少。极性是指膜成分和亚细胞的不对称分配。结构，沿顶基底轴和平面轴定向，对于上皮组织的正确组装和功能至关重要。细胞极性的保存对于肿瘤抑制至关重要，因此具有特殊性。与这个概念一致的是，我们之前发现了一种新颖且意想不到的机制，可以在皮肤表皮的分裂细胞中保持平面极性，同样，这种机制也是由有丝分裂激酶直接控制的。这是控制细胞周期进展并在癌症中失调的机制的首次证明，细胞分裂和平面细胞极性是由相同的调控机制控制的，并且可以解释为什么在癌症中，过度增殖和细胞紊乱如此密切。我们追求细胞周期机制调节细胞极性以确保细胞分裂时的保存，并且使用将哺乳动物遗传学与细胞生物学、蛋白质组学相结合的多方面方法，将细胞周期控制中的极性解耦会损害组织结构和增殖稳态。和延时成像，我们将在表皮发育和再生的背景下解决我们的假设，具体来说，我们将1）定义整个过程中调节平面细胞极性的细胞周期依赖性事件。有丝分裂进展；2）确定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过程中的增殖和分化。在我们对组织结构和生长如何联系的理解中，我们认识到增殖和细胞极性是通过相同的机制联系起来的，了解介导这两个重要细胞生物过程之间串扰的机制将有助于我们根据其对细胞和组织极性的影响，重新评估当前针对细胞周期机制的疗法。