Mechanisms Driving Asymmetric Cell Division in the Epidermis

描述（由申请人提供）： 在胚胎发育期间，单层外胚层细胞层转变为多层表皮。表皮的多层或分层结构对其屏障功能至关重要-使其能够防止脱水和感染。表皮的分层是由不对称的细胞分裂驱动的，细胞分裂产生一个增殖的基底细胞和一个表达分化标志物的基底上细胞。我们想了解表皮细胞如何重新定向其有丝分裂纺锤体，以不对称分裂。实现这一目标的必要的第一步是确定纺锤体重新定向过程中纺锤体极和微管的动力学。我们已经开发了完成这一分析的工具和方法。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以及它的功能是什么仍然不确定。我们将测试NuMA的蛋白质-蛋白质相互作用在其定位于细胞皮质和纺锤体重定向中的功能相关性。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，干细胞稳态，形态发生和免疫反应中发挥着重要作用。此外，已提出破坏不对称分裂以促进肿瘤发生。因此，了解驱动不对称细胞分裂的机制不仅可以深入了解表皮分层，还可以了解其他生理和病理过程。

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.