Department of Physiology Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.
PLoS Biol. 2012 Feb;10(2):e1001256. doi: 10.1371/journal.pbio.1001256. Epub 2012 Feb 7.
The visceral endoderm (VE) is a simple epithelium that forms the outer layer of the egg-cylinder stage mouse embryo. The anterior visceral endoderm (AVE), a specialised subset of VE cells, is responsible for specifying anterior pattern. AVE cells show a stereotypic migratory behaviour within the VE, which is responsible for correctly orientating the anterior-posterior axis. The epithelial integrity of the VE is maintained during the course of AVE migration, which takes place by intercalation of AVE and other VE cells. Though a continuous epithelial sheet, the VE is characterised by two regions of dramatically different behaviour, one showing robust cell movement and intercalation (in which the AVE migrates) and one that is static, with relatively little cell movement and mixing. Little is known about the cellular rearrangements that accommodate and influence the sustained directional movement of subsets of cells (such as the AVE) within epithelia like the VE. This study uses an interdisciplinary approach to further our understanding of cell movement in epithelia. Using both wild-type embryos as well as mutants in which AVE migration is abnormal or arrested, we show that AVE migration is specifically linked to changes in cell packing in the VE and an increase in multi-cellular rosette arrangements (five or more cells meeting at a point). To probe the role of rosettes during AVE migration, we develop a mathematical model of cell movement in the VE. To do this, we use a vertex-based model, implemented on an ellipsoidal surface to represent a realistic geometry for the mouse egg-cylinder. The potential for rosette formation is included, along with various junctional rearrangements. Simulations suggest that while rosettes are not essential for AVE migration, they are crucial for the orderliness of this migration observed in embryos. Our simulations are similar to results from transgenic embryos in which Planar Cell Polarity (PCP) signalling is disrupted. Such embryos have significantly reduced rosette numbers, altered epithelial packing, and show abnormalities in AVE migration. Our results show that the formation of multi-cellular rosettes in the mouse VE is dependent on normal PCP signalling. Taken together, our model and experimental observations suggest that rosettes in the VE epithelium do not form passively in response to AVE migration. Instead, they are a PCP-dependent arrangement of cells that acts to buffer the disequilibrium in cell packing generated in the VE by AVE migration, enabling AVE cells to migrate in an orderly manner.
内胚层（VE）是一种简单的上皮细胞，形成了小鼠胚胎卵圆柱阶段的外层。前内脏内胚层（AVE）是一种特殊的 VE 细胞亚群，负责指定前体模式。AVE 细胞在 VE 内表现出一种典型的迁移行为，这种行为负责正确定向前后轴。在 AVE 迁移过程中，VE 的上皮完整性得以维持，该过程通过 AVE 和其他 VE 细胞的插入发生。尽管是连续的上皮片，但 VE 的两个区域表现出截然不同的行为特征，一个区域显示出强大的细胞运动和插入（AVE 在此迁移），另一个区域是静态的，细胞运动和混合相对较少。关于上皮细胞内细胞重新排列以适应和影响细胞亚群（如 AVE）的持续定向运动的知识很少。本研究采用跨学科方法进一步了解上皮细胞中的细胞运动。使用野生型胚胎以及 AVE 迁移异常或停滞的突变体，我们表明 AVE 迁移与 VE 中细胞包装的变化以及多细胞玫瑰花结排列（五个或更多细胞在一个点相遇）的增加特别相关。为了研究玫瑰花结在 AVE 迁移中的作用，我们开发了一种 VE 中细胞运动的数学模型。为此，我们使用基于顶点的模型，在椭圆表面上实现，以代表小鼠卵圆柱的真实几何形状。包括玫瑰花结形成的可能性，以及各种连接重排。模拟表明，虽然玫瑰花结不是 AVE 迁移所必需的，但对于胚胎中观察到的这种迁移的有序性至关重要。我们的模拟与平面细胞极性（PCP）信号中断的转基因胚胎的结果相似。这样的胚胎玫瑰花结数量明显减少，上皮包装改变，并且 AVE 迁移异常。我们的结果表明，小鼠 VE 中多细胞玫瑰花结的形成依赖于正常的 PCP 信号。总之，我们的模型和实验观察表明，VE 上皮中的多细胞玫瑰花结不是被动形成以响应 AVE 迁移的。相反，它们是细胞的 PCP 依赖性排列，用于缓冲 AVE 迁移在 VE 中产生的细胞包装不平衡，使 AVE 细胞能够有序地迁移。
