Mitotic Rounding and Planar Spindle Alignment in Proliferating Epithelia

 描述(申请人提供)：增殖上皮中的有丝分裂圆形和平面纺锤体排列项目摘要在多细胞动物的发育和动态平衡过程中，增殖上皮细胞的粘附层提供了几乎所有器官形态发生和生理方面必不可少的空间和结构内容。在人类中，上皮细胞增殖控制的缺陷可能导致广泛的病理，包括大约80%的癌症起源于上皮(癌)。然而，尽管了解上皮细胞增殖在发育和疾病中的核心重要性，有丝分裂是如何在空间和时间上与维持上皮结构相协调的仍然知之甚少。在这个方案中，我们利用果蝇的想象盘作为遗传模型来揭示在活体中协调细胞增殖和上皮细胞尖基极化的基本分子和细胞机制。在目标1中，我们使用遗传分析和创新的活体成像方法来研究有丝分裂上皮细胞如何在进入前期时分解其复杂的间期形态，并随后在顶端上皮表面聚集。在目标2中，我们使用遗传学、生物化学和蛋白质组学的方法来询问有丝分裂纺锤体极点和连接定位的肿瘤抑制基因Scribble和Discs Large在体内平面纺锤体排列过程中的相互作用。最后，在目标3中，我们研究了上皮细胞到间充质细胞转变(EMTs)的分子和细胞特征，这些EMTs是由于上皮细胞分裂过程中有丝分裂纺锤体的平面取向缺陷造成的。在这些研究的结论中，我们将极大地扩展我们对上皮细胞分裂和平面纺锤体定向的基础知识，开发出一种新的遗传易处理的模型，用于体内由纺锤体定向缺陷引起的异常EMT事件，并为分子机制提供详细的见解。 对这两个过程的基因控制。

 DESCRIPTION (provided by applicant): Mitotic Rounding and Planar Spindle Alignment in Proliferating Epithelia Project Summary During development and homeostasis of multicellular animals, adherent layers of proliferating epithelial cells provide the spatial and structural contet essential for nearly all aspects of organ morphogenesis and physiology. In humans, defects in the control of epithelial cell proliferation can result in a wide range of pathologies, including te approximate 80% of cancers derived from epithelia (carcinomas). Nevertheless, despite the central importance of understanding epithelial proliferation in development and disease, precisely how mitotic division is spatially and temporally coordinated with the maintenance of epithelial architecture remains poorly understood. In this proposal, we take advantage of Drosophila imaginal discs as a genetic model to uncover fundamental molecular and cellular mechanisms that coordinate cell proliferation with epithelial apico-basal polarization in vivo. In Aim 1 we use genetic analysis and innovative live imaging methods to investigate how mitotic epithelial cells disassemble their complex interphase morphologies at prophase entry and subsequently round up at the apical epithelial surface. In Aim 2 we use genetic, biochemical, and proteomic approaches to interrogate interactions between the mitotic spindle poles and the junction-localized tumor suppressors Scribble and Discs Large during planar spindle alignment in vivo. Lastly, in Aim 3 we investigate the molecular and cellular features of epithelial-to-mesenchymal transitions (EMTs) that result from defective planar orientation of the mitotic spindle during epithelial cell division. At the conclusion of these studies, we will have greatly expanded our fundamental knowledge of epithelial cell division and planar spindle orientation developed a novel genetically-tractable model for abnormal EMT events that result from defective spindle orientation in vivo, and provided detailed mechanistic insight into the molecular genetic control of both of these processes.