Cell-cycle control of cell polarity in epidermal patterning and differentiation

 描述(申请人提供)：细胞极性丧失和侵袭行为被认为是癌症的特征，但令人惊讶的是，人们对在组织生长和更新过程中保持细胞极性的机制知之甚少。极性是指膜组分和亚细胞结构的不对称划分，沿着顶基轴和平面轴方向，对于上皮组织的正确组装和功能是必不可少的。细胞极性的保存在肿瘤抑制中至关重要，因此，当细胞分裂时，必须存在特殊的机制来保存极性。与这一概念一致，我们之前发现了一种新的和意想不到的机制，在分裂皮肤表皮细胞时保持平面极性。最近的数据表明，这种机制直接由有丝分裂酶控制，这是控制细胞周期进展的相同机制，在癌症中被解除调控。这是第一次证明细胞分裂和平面细胞极性是由相同的调控机制控制的，这可能解释了为什么在癌症中，过度增殖和细胞紊乱如此紧密地交织在一起。我们假设，细胞周期机制调节细胞极性，以确保细胞分裂时细胞极性的保存，而将极性从细胞周期控制中分离出来的异常将破坏组织结构和增殖稳态。使用哺乳动物遗传学与细胞生物学、蛋白质组学和时间推移成像相结合的多方面方法，我们将在表皮发育和再生的背景下解决我们的假设。具体地说，我们将1)定义在整个有丝分裂进程中调节平面细胞极性的细胞周期相关事件；2)确定跨表皮的增殖格局如何影响全球平面细胞极性；3)破译平面细胞极性的扰动如何在皮肤发育和动态平衡期间影响增殖和分化。拟议实验的成功完成将使我们对组织结构和生长是如何联系在一起的理解发生转变，人们认识到增殖和细胞极性是通过相同的机制联系在一起的。了解这两个基本细胞生物学过程之间的串扰机制将有助于我们重新评估目前针对细胞周期机制的治疗，因为它们对细胞和组织极性的影响。

 DESCRIPTION (provided by applicant): Loss of cell polarity and invasive behavior are regarded as hallmarks of cancer, but surprisingly little is known about the mechanisms that preserve cell polarity during tissue growth and turnover. 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. Consistent with this notion, we previously discovered a novel and unexpected mechanism that preserves planar polarity in dividing cells of the skin epidermis. More recent data demonstrate this mechanism is controlled directly by mitotic kinases, the same machinery that controls cell cycle progression and is deregulated in cancer. This is the first demonstration that 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. We hypothesize that the cell cycle machinery regulates cell polarity to ensure its preservation when cells divide, and that aberrations uncoupling polarity from cell cycle control will impair tissue architecture and proliferative homeostasis. Using a multifaceted approach combining mammalian genetics with cell biology, proteomics, and time-lapse imaging we will address our hypothesis in the context of epidermal development and regeneration. Specifically we will 1) define the cell cycle- dependent events that regulate planar cell polarity throughout mitotic progression; 2) determine how the landscape of proliferation across the epidermis impacts global planar cell polarity, and 3) decipher how perturbations in planar cell polarity influence proliferation and differentiation durig skin development and homeostasis. Successful completion of the proposed experiments will bring a shift in our understanding of how tissue architecture and growth are connected where it is recognized that proliferation and cell polarity are connected by the same machinery. Understanding the mechanisms that mediate crosstalk between these two essential cell biological processes will help us to reevaluate current therapies that target cell cycle machinery in light of their effects on cell and tissue polarity.