Tension at intercellular junctions is necessary for accurate orientation of cell division in the epithelium plane
Tension at intercellular junctions is necessary for accurate orientation of cell division in the epithelium plane
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DOI：
10.1101/2022.01.30.478396
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发表时间：
2022-01
影响因子：
11.1
通讯作者：
Ana Lisica;J. Fouchard;M. Kelkar;T. Wyatt;J. Duque;Anne-Betty Ndiaye;A. Bonfanti;B. Baum;A. Kabla;G. Charras
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文献类型：
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作者：
Ana Lisica;J. Fouchard;M. Kelkar;T. Wyatt;J. Duque;Anne-Betty Ndiaye;A. Bonfanti;B. Baum;A. Kabla;G. Charras
细胞分裂的方向由其有丝分裂纺锤体的方向决定，对决定细胞命运、控制组织形状和维持组织结构很重要。垂直于底物平面的分裂可以促进组织在发育或伤口愈合过程中的分层，但当取向异常时也会发生转移。关于设置纺锤体取向所涉及的分子机制，我们知道得很多。然而，尽管上皮细胞持续受到机械应力，但机械因素（如组织张力）在确保上皮平面内纺锤体取向方面的作用却知之甚少。在这里，我们使用缺乏细胞外基质的悬浮上皮单层，并受到不同水平的组织张力来研究相对于组织平面的分裂方向。我们发现，通过压缩单层或抑制肌球蛋白收缩性来降低组织张力会导致更高的面外分裂频率。反过来，通过增加细胞收缩性或组织拉伸来增加组织张力，可以恢复精确的平面内分裂。通过考虑上皮的完整三维几何形状，我们表明纺锤体对组织张力敏感，独立于细胞形状，通过其对亚细胞表面张力的影响。总的来说，我们的数据表明，在上皮平面上准确的纺锤体取向需要在细胞间连接处存在足够大的张力。在生长的上皮细胞中，分裂通常在组织平面上定向以驱动扩张。在一些器官中，分裂重新定向，使它们垂直于上皮平面，以驱动组织分层和细胞分化。当不受控制时，这种方向的转换会导致组织缺陷，在癌症中，可能会导致转移。虽然对控制有丝分裂纺锤体取向的分子机制了解很多，但对机械因素的作用知之甚少。在这里，我们使用力学和化学扰动来表明力学在控制分割平面中起作用。总的来说，我们的数据表明，纺锤体在上皮平面上的定向需要在细胞间连接处有足够的张力。
The direction in which a cell divides is set by the orientation of its mitotic spindle and is important for determining cell fate, controlling tissue shape and maintaining tissue architecture. Division perpendicular to the plane of the substrate can promote tissue stratification during development or wound healing, but also metastasis when orientation is aberrant. Much is known about the molecular mechanisms involved in setting the spindle orientation. However, less is known about the contribution of mechanical factors, such as tissue tension, in ensuring spindle orientation in the plane of the epithelium, despite epithelia being continuously subjected to mechanical stresses. Here, we used suspended epithelial monolayers devoid of extracellular matrix and subjected to varying levels of tissue tension to study the orientation of division relative to the tissue plane. We found that decreasing tissue tension by compressing the monolayers or by inhibiting myosin contractility leads to a higher frequency of out-of-plane divisions. Reciprocally, accurate in-plane division can be restored by increasing tissue tension by increasing cell contractility or by tissue stretching. By considering the full three-dimensional geometry of the epithelium, we show that spindles are sensitive to tissue tension, independently of cell shape, through its impact on the tension at subcellular surfaces. Overall, our data suggest that accurate spindle orientation in the plane of the epithelium necessitates the presence of a sufficiently large tension at intercellular junctions. Significance statement In growing epithelia, divisions are typically oriented in the plane of the tissue to drive expansion. In some organs, divisions are then re-oriented so that they occur perpendicular to the epithelium plane to drive tissue stratification and cell differentiation. When uncontrolled, this switch in orientation can lead to defects in tissue organisation and, in cancer, likely contribute to metastasis. While much is known about the molecular mechanisms controlling mitotic spindle orientation, less is known about the role of mechanical factors. Here we use mechanical and chemical perturbations to show that mechanics plays a role in controlling the plane of division. Overall, our data suggest that the orientation of spindles in the epithelium plane requires sufficient tension across intercellular junctions.