Cell cycle regulation of polarity proteins in proliferating epithelia

项目摘要 上皮是粘附细胞的极化层，是动物生长过程中出现的第一个有组织的集合体。 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， 在动物的一生中不断增殖。一个长期存在的问题是增殖细胞如何维持其 上皮组织细胞周期控制和上皮组织的丧失导致组织变形 和上皮癌。特别是细胞极性的丧失是上皮细胞性白血病最普遍的原因之一。 组织混乱我们的中心假设是上皮细胞极性受细胞周期控制。工作 海葵Nematostella vectensis的增殖上皮细胞显示，极性蛋白在 并与细胞周期一致地离开顶端结构域。在不同的宇宙中发现类似的极性振荡 上皮细胞表明上皮极性的细胞周期调节是广泛保守的。然而，很少有 了解驱动上皮极性振荡的机制及其在组织稳态中的作用。我 建议使用Nematostella的早期发育胚胎来研究细胞周期如何调节 上皮极性Nematostella胚胎在最初的几次卵裂中形成极化层， 在随后的同步细胞分裂期间组织。成像和分子生物学方法将 [1]剖析细胞周期机制是否以及如何直接修饰顶端极性蛋白， [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振荡。的 我们将揭示的机制可能广泛适用于其他动物，并与人类有关。 上皮及其相关疾病。 .

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. .