Regulation of cell adhesion during planer polarity organization in the epidermis

描述（由申请人提供）：细胞如何决定它们组织的方向，它们使用什么信号来传递这些信息？上皮细胞沿两个方向组织：顶基轴和垂直于顶基轴的平面，称为平面细胞极性（PCP）。尽管细胞极性的破坏在转移性癌症中起直接作用，但启动PCP信号的机制尚不清楚，细胞粘附调节在建立细胞极性中的作用尚未在体内研究。该项目的长期目标是了解复杂上皮组织中细胞粘附是如何调节的，确定细胞外信号是否在这种调节中起作用，以及适当的PCP是否需要调节细胞粘附。我们计划验证这一假设，即控制顶基细胞极性和PCP的途径共同影响细胞-细胞接触，更具体地说，通过影响粘附连接的空间和时间分布。控制细胞顶基极性和平面极性的信号通路在物种中都是高度保守的，但受这些通路影响的下游细胞功能在不同的细胞类型中差异很大。我希望通过研究这些过程没有很好表征的组织来揭示建立细胞极性的新机制。因此，我们最近开始利用果蝇胚胎的腹侧表皮来研究控制PCP的分子机制。使用胚胎使我们能够专门测试粘附连接和极性蛋白的作用，这些蛋白在先前用于研究PCP的系统中导致细胞致命。总之，我们的初步数据表明，控制细胞极性两个轴的途径共同作用以稳定和分离细胞粘附连接，并且这种细胞粘附的动态调节是发育上皮组织中适当极性所必需的。相关性：控制上皮细胞稳定性的机制尚不清楚，尽管细胞-细胞接触的解离直接参与上皮细胞的转移转化，90%的癌症死亡是由原发肿瘤的转移引起的。此外，目前还没有有效预防转移的药物治疗方法。由于转移性肿瘤最明显的形态学变化直接涉及上皮特异性细胞连接蛋白的下调，因此该项目将为转移性癌症的分子机制提供重要的见解。

DESCRIPTION (provided by applicant): How do cells determine the direction of their organization, and what signals do they use to communicate this information? Epithelial cells are organized in two directions: the apical-basal axis and the plane perpendicular to this axis, which is referred to as planar cell polarity (PCP). Despite the direct role that breakdown of cell polarity plays in metastatic cancer, the mechanisms that initiate PCP signaling are not well understood and the role that regulation of cellular adhesion plays in establishing cell polarity has not been investigated in vivo. The long-term goals of this project are to understand how cellular adhesion is regulated in complex epithelial tissues, to determine whether extracellular signals play a part in this regulation, and whether regulation of cell adhesion is required for proper PCP. We plan to test the hypothesis that the pathways that control apical-basal cell polarity and PCP work together to affect cell-cell contact and more specifically, by affecting the spatial and temporal distribution of adherens junctions. The signaling pathways that control apical-basal and planar cell polarity are both highly conserved among species, but the downstream cellular functions that are affected by these pathways vary greatly among different cell types. I hope to uncover novel mechanisms of establishing cell polarity by studying a tissue in which these processes are not well-characterized. Therefore, we have recently begun using the ventral epidermis of the Drosophila embryo to study the molecular mechanisms that control PCP. Using the embryo has allowed us to specifically test the roles of adherens junctions and polarity proteins that cause cell lethality in the systems previously used to study PCP. Altogether, our preliminary data suggest that the pathways that control both axes of cell polarity work together to stabilize and dissociate cellular adhesion junctions, and that this dynamic regulation of cell adhesion is required for the proper polarity in developing epithelial tissues. Relevance: The mechanisms that control epithelial stability are not well understood, even though the dissociation of cell-cell contacts is directly involved in the metastatic transformation of epithelial cells and 90% of all cancer deaths are caused by metastasis of primary tumors. In addition, there is no current medical treatment that can usefully prevent metastasis. This project will contribute important insights into the molecular mechanisms that go awry in metastatic cancers, since the most apparent morphological change of metastatic tumors directly involves the downregulation of epithelial-specific cellular junction proteins that we will be investigating.