Cell cycle control of cell polarity and fate in epidermal morphogenesis

细胞极性丧失和侵袭行为是癌症的特征，但细胞极性是如何保持的 在组织生长和周转期间，人们对此知之甚少。极性指的是不对称划分 膜组件和亚细胞结构沿顶基和平面轴方向， 对于上皮组织的正确组装和功能是必不可少的。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存 细胞分裂时的极性。我们已经证明，为了保护组织结构，上皮极性是 当细胞分裂时动态重塑。不对称定位的极性蛋白质暂时 通过大量内吞进入细胞质而从细胞表面移除。除法后，它们被回收利用 到表面，在那里极性被恢复。这一机制直接由有丝分裂酶控制，即 同样的机制，控制细胞周期进程，并在癌症中放松调控。因此，细胞分裂和 平面细胞的极性由相同的调控机制控制，这可能解释了为什么在癌症中， 过度增殖和细胞紊乱是如此紧密地交织在一起。 在本提案中，我们建立并扩展了这项基础性工作，以研究细胞的极性如何 有丝分裂后恢复，以及细胞分裂如何促进强健和排列的组织的建立 两极。我们将利用我们在实时和超分辨率成像方面的最新技术进步 破译有丝分裂后恢复极性的运输机制以及有丝分裂的方式 复极化建立了组织尺度的极性；2)定义了指导有丝分裂复极化的空间线索； 以及3)确定相邻细胞如何协调有丝分裂移除细胞间连接 内吞作用。成功完成我们的目标将揭示高度 增殖性上皮可保持组织的完整性。

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.