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.

细胞极性和侵入性行为的丧失是癌症的标志，但如何保留细胞极性 在组织生长和周转期间，人们了解得很糟糕。极性是指不对称分区 膜成分和亚细胞结构沿着apicobasal和平面轴定向， 并且对于上皮组织的适当组装和功能至关重要。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存 细胞分裂时极性。我们已经表明，为了保存组织结构，上皮极性是 细胞分裂时动态重塑。非对称局部极性蛋白暂时是 通过大量内吞作用从细胞表面移入细胞质。分裂后，它们被回收 到恢复极性的表面。该机制由有丝分裂激酶直接控制 控制细胞周期进展并在癌症中进行管制的机械。因此，细胞分裂和 平面细胞极性由相同的调节机制控制，并且可以解释为什么在癌症中， 高增殖和细胞疾病紧密相互交织。 在此提案中，我们建立并扩展了这项基础工作，以研究细胞极性的方式 有丝分裂后恢复以及细胞分裂如何促进稳健和对齐组织的建立 极性。我们将利用我们最近在现场和超分辨率成像中的技术进步 皮肤至1）破译有丝分裂后恢复极性的传输机制以及有丝分裂的方式 重极化建立了组织尺度的极性。 2）定义直接有丝分裂复极化的空间提示； 3）确定相邻细胞如何协调通过 跨内聚细胞增多。成功完成我们的目标将揭示高度高度的机制 增殖性上皮保留组织完整性。