Department of Biology, Stanford University, Stanford, CA 94305.
Biophysics Program, Stanford University, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):E5845-E5853. doi: 10.1073/pnas.1701703114. Epub 2017 Jul 3.
Tissue morphogenesis requires the coordinated regulation of cellular behavior, which includes the orientation of cell division that defines the position of daughter cells in the tissue. Cell division orientation is instructed by biochemical and mechanical signals from the local tissue environment, but how those signals control mitotic spindle orientation is not fully understood. Here, we tested how mechanical tension across an epithelial monolayer is sensed to orient cell divisions. Tension across Madin-Darby canine kidney cell monolayers was increased by a low level of uniaxial stretch, which oriented cell divisions with the stretch axis irrespective of the orientation of the cell long axis. We demonstrate that stretch-induced division orientation required mechanotransduction through E-cadherin cell-cell adhesions. Increased tension on the E-cadherin complex promoted the junctional recruitment of the protein LGN, a core component of the spindle orientation machinery that binds the cytosolic tail of E-cadherin. Consequently, uniaxial stretch triggered a polarized cortical distribution of LGN. Selective disruption of engagement of E-cadherin in an otherwise cohesive cell monolayer, or loss of LGN expression, resulted in randomly oriented cell divisions in the presence of uniaxial stretch. Our findings indicate that E-cadherin plays a key role in sensing polarized tensile forces across the tissue and transducing this information to the spindle orientation machinery to align cell divisions.
组织形态发生需要细胞行为的协调调节，其中包括决定子细胞在组织中位置的细胞分裂方向。细胞分裂方向由局部组织环境中的生化和机械信号指示，但这些信号如何控制有丝分裂纺锤体方向尚不完全清楚。在这里，我们测试了如何感知上皮细胞单层中的机械张力以定向细胞分裂。通过低水平的单轴拉伸增加了 Madin-Darby 犬肾细胞单层中的张力，该拉伸无论细胞长轴的方向如何，都使细胞分裂具有拉伸轴的方向。我们证明，拉伸诱导的分裂方向需要通过 E-钙粘蛋白细胞-细胞黏附进行机械转导。E-钙粘蛋白复合物上张力的增加促进了 LGN 蛋白的连接募集，LGN 是纺锤体定向机制的核心组成部分，它结合 E-钙粘蛋白的细胞质尾部。因此，单轴拉伸引发了 LGN 的极化皮质分布。在单轴拉伸存在的情况下，选择性破坏细胞单层中 E-钙粘蛋白的结合或 LGN 表达的丧失导致细胞分裂随机定向。我们的发现表明，E-钙粘蛋白在感知跨组织的极化拉伸力以及将此信息转导至纺锤体定向机制以对准细胞分裂方面发挥着关键作用。
