Mechanisms Driving Asymmetric Cell Division in the Epidermis

描述(由申请人提供)： 在胚胎发育过程中，单层外胚层细胞层转化为多层表皮。表皮的多层或分层结构对于其屏障功能至关重要--使其能够防止脱水和感染。表皮的层化是由不对称的细胞分裂驱动的，这种分裂产生一个增殖的基底细胞和一个表达分化标记的超基底细胞。我们想了解表皮细胞如何调整其有丝分裂纺锤体的方向，以实现不对称分裂。迈向这一目标的必要的第一步是定义纺锤体极和微管在纺锤体重定向过程中的动力学。我们已经开发了工具和方法来完成这一分析。在分子水平上，NUMA是不对称细胞分裂机制的核心组成部分。在无脊椎动物中，它是不对称细胞分裂所必需的，尽管它是如何定位的，它的功能还不确定。我们将测试NUMA的蛋白质-蛋白质相互作用在其对细胞皮质的定位和纺锤体重新定位方面的功能相关性。这项工作将具有广泛的意义，因为不对称分裂在细胞类型多样化、干细胞动态平衡、形态发生和免疫反应中发挥着基础性作用。此外，中断不对称分裂也被提出用来促进肿瘤的发生。因此，了解推动细胞不对称分裂的机制将不仅为深入了解表皮分层，而且还将提供额外的生理和病理过程。

DESCRIPTION (provided by applicant): During embryonic development, a single-layered ectodermal cell layer transforms into a multi- layered epidermis. The multi-layered or stratified architecture of the epidermis is essential for its barrier function - allowing it to prevent both dehydration and infection. Stratification of the epidermis is driven by asymmetric cell divisions that generate one proliferative basal cell and one suprabasal cell that expresses differentiation markers. We want to understand how epidermal cells reorient their mitotic spindle in order to divide asymmetrically. A necessary first step toward this goal is to define the dynamics of both spindle poles and microtubules during the process of spindle reorientation. We have developed the tools and methodologies to complete this analysis. On the molecular level, NuMA is a core component of the asymmetric cell division machinery. In invertebrates, it is required for asymmetric cell divisions, though how it is localized and what its function is remains undetermined. We will test the functional relevance of NuMA's protein-protein interactions in both its localization to the cell cortex and in spindle reorientation. The work proposed will have broad significance as asymmetric divisions play fundamental roles in cell-type diversification, stem cell homeostasis, morphogenesis and the immune response. Additionally, disruption of asymmetric divisions has been proposed to promote tumorigenesis. Therefore, understanding the mechanisms driving asymmetric cell division will provide insights not only into epidermal stratification but also additional physiological and pathological processes.