Cell cycle regulation of polarity proteins in proliferating epithelia

项目总结 上皮是两极分化的贴壁细胞层，是动物体内出现的第一批有组织的集合体 发展。由于它们构成了大多数器官的支架，它们经历了广泛的重塑和 在动物的一生中不断繁殖。一个长期存在的问题是，增殖细胞如何维持其 上皮性组织。细胞周期控制和上皮组织的丧失都会导致组织变形 和上皮性癌症。尤其是，细胞极性的丧失是上皮样病变最常见的原因之一。 组织混乱。我们的中心假设是上皮极性受控于细胞周期。工作于 海葵线虫的增殖上皮显示，极性蛋白振荡在 并与细胞周期一致地脱离顶端区域。在不同种类的晶体中发现相似的极性振荡 上皮细胞提示细胞周期对上皮极性的调控是广泛保守的。然而，很少有 已知驱动上皮极性振荡的机制及其在组织动态平衡中的作用。我 建议使用线虫的早期发育胚胎来研究细胞周期是如何调节的 上皮极性。线虫胚胎在最初的几个卵裂中形成极化的层，并保持这一点 在随后的同步单元分裂期间的组织。成像和分子生物学方法将 允许我们：[1]剖析细胞周期机制是否以及如何直接修改顶端极性蛋白质，以及 [2]确定细胞骨架组织中有丝分裂的变化如何控制顶端蛋白质的振荡。这个 我们将揭示的机制很可能广泛适用于其他动物，并与人类相关 上皮细胞及其相关疾病。 。

PROJECT SUMMARY Epithelia are polarized layers of adherent cells and the first organized assemblies to emerge during animal development. As they constitute the scaffolds of most organs, they undergo extensive remodeling and proliferation throughout the life of the animal. A long-standing question is how proliferating cells maintain their epithelial organization. Loss of both cell cycle control and epithelial organization result in tissue deformations and epithelial cancers. Loss of cell polarity, in particular, is one of the most prevalent causes of epithelial disorganization. Our central hypothesis is that epithelial polarity is under cell cycle control. Work on proliferative epithelia of the sea anemone Nematostella vectensis has shown that polarity proteins oscillate on and off the apical domain in concert with the cell cycle. Discovery of similar polarity oscillations in various epithelia suggest that cell cycle regulation of epithelial polarity is broadly conserved. However, very little is known about the mechanisms that drive epithelial polarity oscillations and their role in tissue homeostasis. I propose to use the early developing embryos of Nematostella to investigate how the cell cycle regulates epithelial polarity. Nematostella embryos form polarized layers within the first few cleavages and maintain this organization during subsequent synchronous cell divisions. Imaging and molecular biological approaches will allow us to: [1] Dissect whether and how the cell cycle machinery directly modifies apical polarity proteins, and [2] Determine how mitotic changes in cytoskeletal organization control apical protein oscillations. The mechanisms we will uncover are likely to be broadly applicable in other animals and relevant for human epithelia and their associated diseases. .