Role of JAM family adhesion molecules in epithelial cell extrusion

上皮组织排列在身体和器官表面，形成多细胞生物体内部和外部环境之间的边界。某些上皮，如皮肤的复层上皮或内衬在肠道或肺部管腔表面的简单上皮，不断暴露在物理、化学或生物性质的环境因素(如紫外线、毒素或病原体)中，造成基因组改变的风险，最终可能导致癌症生长。一种可能已经进化出来的防止衰老过程中基因组变化积累的机制是用新细胞取代老化的细胞。在这个被称为细胞周转的过程中，终末分化的细胞被新形成的成年干细胞所取代。细胞周转率在面向外部的上皮中特别高，例如皮肤或小肠内壁的那些。细胞周转是通过一个称为细胞挤出的过程实现的，在这个过程中，活的或凋亡的细胞被从上皮层驱逐出去。细胞挤出必须是一个严格调控的过程，因为挤出失败或沿着错误的(即基底部)方向挤出可能会导致癌细胞的生长和转移。调节细胞挤出的分子机制尚不清楚。挤出细胞与相邻细胞连接处的细胞黏附分子很可能直接参与了细胞挤出过程。我们的兴趣集中在一类细胞黏附分子上，即连接黏附分子(JAMs)。一些堵塞局限于上皮细胞-细胞连接处，一些堵塞集中在紧密连接处。在以前的研究中，我们已经确定了JAMs的一系列功能，例如，在调节细胞-细胞接触和紧密连接形成中的作用，调节细胞的极性，以及调节有丝分裂纺锤体的方向。在这个项目中，我们研究了JAMs在上皮细胞挤出过程中的作用。这项建议的具体目标是：(1)确定调节上皮细胞挤出的JAMs家族成员；(2)确定JAMs的结合伙伴，通过JAMs调节上皮细胞挤出；(3)阐明JAMs在调节上皮细胞挤出过程中肌动球蛋白收缩性能中的作用。

Epithelial tissues line the body and organ surfaces and form the boundaries between the internal and external environment of multicellular organisms. Certain epithelia such as the stratified epithelium of the skin or the simple epithelia lining the luminal surface of the gut or of the lung are constantly exposed to environmental factors of physical, chemical, or biological nature (e.g. UV-light, toxins, or pathogens), imposing the risk of alterations in the genome which could ultimately lead to cancerous growth. One mechanism that has probably evolved to prevent the accumulation of genome alterations during aging is to replace aged cells by new cells. During this process called Cell Turnover, terminally differentiated cells are replaced by cells newly formed from adult stem cells. The rate of cell turnover is particularly high in epithelia facing the exterior, such as those of the skin or those lining the small intestine. Cell turnover is achieved by a process called Cell Extrusion, during which cells - either living or apoptotic - are expelled from the epithelial layer. Cell extrusion must be a tightly regulated process since failure of extrusion, or extrusion in the wrong (i.e. basal) direction, could lead to cancerous growth and metastasis. The molecular mechanisms that regulate cell extrusion are poorly understood. It is very likely that cell adhesion molecules at the junctions between the extruded cell and its neighbours are directly involved in cell extrusion. Our interest is focused on a family of cell adhesion molecules, the Junctional Adhesion Molecules (JAMs). Several JAMs are localized at epithelial cell-cell junctions, and some JAMs are enriched at the tight junctions. In previous studies we have identified a diverse range of functions for JAMs, for example a role in the regulation of cell-cell contact and tight junction formation, the regulation of cell polarity, and the regulation of mitotic spindle orientation. In this project, we investigate the role of JAMs during epithelial cell extrusion. The specific objectives of this proposal are: (1) identify JAM family members which regulate epithelial cell extrusion; (2) identify binding partners for JAMs through which JAMs could regulate epithelial cell extrusion; (3) address a role for JAMs in the regulation of actomyosin contractility during epithelial cell extrusion.