Cell cycle control of cell polarity and fate in epidermal morphogenesis

表皮形态发生中细胞极性和命运的细胞周期控制

• 批准号: 10608036
• 负责人: Danelle N Devenport
• 金额: $ 57.5万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-16 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608036
• 关键词: Adhesives; Architecture; Behavior; Binding; Carcinoma; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Polarity; Cell Surface Proteins; Cell division; Cell physiology; Cell surface; Cells; Cellular biology; Complex; Cues; Cytoplasm; Cytoskeleton; Dehydration; Destinations; Disease; Endocytosis; Ensure; Epithelium; Excision; Growth; Impairment; Inflammatory; Inherited; Injury; Intercellular Junctions; Intracellular Transport; Life; Maintenance; Malignant Neoplasms; Mechanics; Membrane; Memory; Microtubules; Mitosis; Mitotic; Morphogenesis; Phosphotransferases; Positioning Attribute; Process; Proliferating; Proteins; Role; Skin; Subcellular structure; Surface; Testing; Tissue Preservation; Tissues; Tumor Suppression; Vesicle; Work; cell cortex; defined contribution; epidermis cell; epithelial repair; in vivo; insight; mouse model; pathogen; planar cell polarity; preservation; skin disorder; stem cells; superresolution imaging; trafficking

Loss of cell polarity and invasive behavior are hallmarks of cancer, but how cell polarity is preserved during tissue growth and turnover is poorly understood. 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. We have shown that to preserve tissue architecture, epithelial polarity is dynamically remodeled when cells divide. Asymmetrically localized polarity proteins are temporarily removed from the cell surface via bulk endocytosis into the cytoplasm. After division, they are recycled to the surface where polarity is restored. This mechanism is controlled directly by mitotic kinases, the same machinery that controls cell cycle progression and is deregulated in cancer. Thus, 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. In this proposal we build and expand on this foundational work to investigate how cell polarity is restored after mitosis and how cell division facilitates the establishment of robust and aligned tissue polarity. We will capitalize on our recent technical advancements in live and super-resolution imaging of the skin to 1) decipher the transport mechanisms that restore polarity following mitosis and how mitotic repolarization establishes tissue-scale polarity; 2) define the spatial cues that direct mitotic repolarization; and 3) determine how neighboring cells coordinate mitotic removal of intercellular junctions via transendocytosis. Successful completion of ours aims will uncover the mechanisms by which a highly proliferative epithelium preserves tissue integrity.

细胞极性丧失和侵袭性行为是癌症的标志，但细胞极性是如何保持的呢？ 在组织生长和周转过程中的作用知之甚少。极性指的是 膜组分和亚细胞结构，沿着顶基轴和平面轴取向， 并且对于上皮组织的正确组装和功能是必需的。细胞极性的保存 在肿瘤抑制中至关重要，因此，必须存在特殊的机制来保护 细胞分裂时的极性。我们已经表明，为了保持组织结构，上皮极性是 在细胞分裂时动态重塑。不对称定位的极性蛋白质暂时 通过大量内吞作用从细胞表面去除到细胞质中。分裂后，它们被回收 到极性恢复的表面。这一机制直接由有丝分裂激酶控制， 与控制细胞周期进程并在癌症中失调的机制相同。因此，细胞分裂和 平面细胞极性由相同的调节机制控制，这可以解释为什么，在癌症中， 细胞过度增殖和细胞紊乱是紧密交织在一起的。 在本提案中，我们在这项基础工作的基础上进行了扩展，以研究细胞极性如何变化 有丝分裂后恢复，以及细胞分裂如何促进建立坚固和对齐的组织 极性我们将利用我们最近在实时和超分辨率成像方面的技术进步， 皮肤1）破译有丝分裂后恢复极性的运输机制，以及有丝分裂如何 复极化建立组织尺度的极性; 2）定义空间线索，指导有丝分裂复极化; 和3）确定相邻细胞如何协调细胞间连接的有丝分裂去除， 转内吞作用成功地完成我们的目标将揭示一个高度 增殖上皮保持组织完整性。