Epithelial organ shape is generated by patterned actomyosin contractility and maintained by the extracellular matrix
Epithelial organ shape is generated by patterned actomyosin contractility and maintained by the extracellular matrix
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DOI：
10.1371/journal.pcbi.1008105
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发表时间：
2020-01
影响因子：
4.3
通讯作者：
Ali Nematbakhsh;Megan Levis;Nilay Kumar;Weitao Chen;Jeremiah J Zartman;M. Alber
中科院分区：
文献类型：
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作者：
Ali Nematbakhsh;Megan Levis;Nilay Kumar;Weitao Chen;Jeremiah J Zartman;M. Alber
在发育过程中，上皮片在定义器官结构方面发挥着重要作用。在这里，我们使用迭代实验和多尺度计算建模方法来解耦肌球蛋白产生的力、核定位、细胞外基质(ECM)和细胞-细胞黏附在形成果蝇翅膀成像盘中的直接和间接影响，这是一个阐明上皮形态发生的一般原理的强大系统。碱基产生的肌球蛋白力被发现调节顶端偏向的核定位，并且是翼盘囊上皮弯曲和细胞伸长所必需的。然而，令人惊讶的是，对岩石驱动的肌动球蛋白收缩性能的短期药物抑制并不影响组织高度或弯曲形状的维持。相比之下，细胞外基底膜的相对紧张性也是在翼盘的区域之间形成的。然而，计算模拟表明，ECM紧张度的图案化只对调节组织形状提供了很小的贡献。相反，被动ECM预应变的积累在形状保持中起着主要作用。令人惊讶的是，这与肌动球蛋白收缩能力的维持无关。此外，翼盘内两层细胞层之间的局部根尖粘连需要在缺乏基础细胞外基质的情况下由岩石驱动的肌球蛋白活性。两层细胞层之间的这种根尖粘连提供了额外的机械支持，以帮助维持组织的完整性。实验和计算相结合的方法提供了关于亚细胞力是如何在单个细胞内产生和维持以诱导组织弯曲的一般洞察，并提出了上皮器官发生的重要设计原则，根据该原则，由肌动球蛋白产生的力随后作为ECM内的预应变维持是相互关联的，但在功能上是可分离的。意义陈述发育生物学中一个突出的主要问题是阐明器官形状形成和维持的一般原理。在这里，迭代的实验和多尺度计算建模方法表明，肌动球蛋白的收缩能力产生沿前后轴的弯曲轮廓，而ECM内的张力对于保持弯曲的形状是充分和必要的，即使一旦形状产生后，没有持续的肌球蛋白收缩能力也是如此。在这项研究中测试的机制确定了建立翼盘形状的必要因素，该翼盘后来在蛹发育过程中形成成虫的翅膀。该方法可以扩展到测试由几个细胞层和ECM层组成的其他上皮系统的新机制。
Epithelial sheets play important roles in defining organ architecture during development. Here, we employed an iterative experimental and multi-scale computational modeling approach to decouple direct and indirect effects of actomyosin-generated forces, nuclear positioning, extracellular matrix (ECM), and cell-cell adhesion in shaping Drosophila wing imaginal discs, a powerful system for elucidating general principles of epithelial morphogenesis. Basally generated actomyosin forces are found to regulate apically biased nuclear positioning and are required for generating epithelial bending and cell elongation of the wing disc pouch. Surprisingly, however, short-term pharmacological inhibition of ROCK-driven actomyosin contractility does not impact the maintenance of tissue height or curved shape. In comparison, the relative tautness of the extracellular basement membrane is also patterned between regions of the wing disc. However, computational simulations show that patterning of ECM tautness provides only a minor contribution to modulating tissue shape. Instead, the buildup of a passive ECM pre-strain serves a principle role in shape maintenance. Surprisingly, this is independent from the maintenance of actomyosin contractility. Furthermore, localized apical adhesion between the two cell layers within the wing disc requires ROCK-driven actomyosin activity in the absence of the basal extracellular matrix. This apical adhesion between the two cell layers provides additional mechanical support to help maintain tissue integrity. The combined experimental and computational approach provides general insight into how the subcellular forces are generated and maintained within individual cells to induce tissue curvature and suggests an important design principle of epithelial organogenesis whereby forces generated by actomyosin followed by maintenance as pre-strain within the ECM are interconnected, but functionally separable. Significance statement A major outstanding question in developmental biology is the elucidation of general principles of organ shape formation and maintenance. Here, an iterative experimental and multi-scale computational modeling approach reveals that actomyosin contractility generates the bent profile along the anterior-posterior axis while tension within the ECM is sufficient and necessary for preserving the bent shape even in the absence of continued actomyosin contractility once the shape is generated. The mechanisms tested in this study define the necessary factors for establishing the shape of the wing disc, which later everts to form the adult wing during pupal development. The method can be extended to test novel mechanisms of other epithelial systems that consist of several cellular and ECM layers.