Endodermal cells use contact inhibition of locomotion to achieve uniform cell dispersal during zebrafish gastrulation.

Jesselynn LaBelle, Tom Wyatt, Stephanie Woo
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Abstract

The endoderm is one of the three primary germ layers that ultimately gives rise to the gastrointestinal and respiratory epithelia and other tissues. In zebrafish and other vertebrates, endodermal cells are initially highly migratory with only transient interactions among one other, but later converge together to form an epithelial sheet. Here, we show that during their early, migratory phase, endodermal cells actively avoid each other through contact inhibition of locomotion (CIL), a characteristic response consisting of 1) actin depolymerization and membrane retraction at the site of contact, 2) preferential actin polymerization along a cell-free edge, and 3) reorientation of migration away from the other cell. We found that this response is dependent on the Rho GTPase RhoA. Expression of dominant-negative (DN) RhoA attenuated migration reorientation after cell-cell contact and increased the amount of time cells spent in contact with each other - behaviors consistent with a loss of CIL. Computational modeling predicted that CIL is required to achieve the efficient and uniform dispersal characteristic of endodermal cells. Consistent with our model, we found that loss of CIL via DN RhoA expression resulted in irregular clustering of cells within the endoderm. Finally, using a combination of pharmacological and genetic perturbations, we identify EphA2 as the cell surface receptor mediating endodermal CIL. Together, our results suggest that endodermal cells use EphA2- and RhoA-dependent CIL as a cell dispersal and spacing mechanism, demonstrating how tissue-scale patterns can emerge from local cell-cell interactions.

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在斑马鱼原肠胚形成过程中,内胚层细胞利用对运动的接触抑制来实现细胞的均匀扩散。
内胚层是三个主要胚层之一,最终形成胃肠道、呼吸道上皮和其他组织。在斑马鱼和其他脊椎动物中,内胚层细胞最初高度迁移,彼此之间只有短暂的相互作用,但后来聚集在一起形成上皮层。在这里,我们发现,在其早期迁移阶段,内胚层细胞通过运动的接触抑制(CIL)主动避开彼此,这是一种特征性反应,包括1)肌动蛋白解聚和接触部位的膜回缩,2)沿着无细胞边缘的肌动蛋白优先聚合,以及3)迁移远离其他细胞的重新定向。我们发现,这种反应依赖于Rho-GTPase-RhoA和EphA/ephrin-A信号传导——显性阴性(DN)RhoA的表达或用EphA抑制剂达沙替尼治疗导致与CIL损失一致的行为,包括接触持续时间增加和接触后迁移重新定向的可能性降低。计算模型预测,需要CIL来实现内胚层细胞的有效和均匀的扩散特性。与我们的模型一致,我们发现通过DN RhoA表达的CIL损失导致内胚层内细胞的不规则聚集。总之,我们的研究结果表明,内胚层细胞使用EphA2-和RhoA依赖性CIL作为细胞扩散和间隔机制,证明了局部相互作用如何产生组织规模的模式。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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