Hydraulic control of embryo size, tissue shape and cell fate
Hydraulic control of embryo size, tissue shape and cell fate
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DOI：
10.1101/389619
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发表时间：
2018-08
期刊：
影响因子：
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通讯作者：
C. J. Chan;M. Costanzo;Teresa Ruiz-Herrero;Gregor Mönke;R. Petrie;L. Mahadevan;T. Hiiragi
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文献类型：
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作者：
C. J. Chan;M. Costanzo;Teresa Ruiz-Herrero;Gregor Mönke;R. Petrie;L. Mahadevan;T. Hiiragi
大小控制是组织发育和内环境稳定的基础1，2。虽然细胞增殖在这一过程中的作用已被广泛研究3，但器官大小控制的机制及其如何影响细胞命运仍不清楚。在这里，我们使用小鼠胚泡发育作为一个模型来揭示充满液体的管腔在胚胎大小控制和细胞命运指定中的关键作用。我们发现，在胚泡扩张期间，管腔的压力增加了两倍，这转化为管腔内滋养外胚层(TE)细胞的皮质张力随之增加。皮质张力的增加导致纽蛋白机械感应和功能紧密连接的成熟，从而建立一个正反馈环路来适应管腔的生长。然而，当皮质张力达到临界阈值时，细胞与细胞之间的黏附不能持续，有丝分裂进入会导致TE上皮破裂、液体渗漏和胚泡塌陷。一个简单的液压门控振荡理论整合了这些反馈交互作用，概括了空洞大小的演变，并预测了胚胎大小与组织体积的比例。我们的理论进一步预测，皮质张力的降低或紧密连接的中断，以及组织硬度的增加会导致胚胎尺寸变小。这些预测通过胚胎的胚胎学、药理学和遗传学操作得到了实验验证。值得注意的是，在不改变组织体积的情况下，这些管腔大小的变化会导致组织结构和细胞命运的改变。总体而言，我们的研究揭示了管腔压力和组织力学如何在组织尺度上控制胚胎的大小，进而在细胞尺度上耦合到细胞的位置和命运。
Size control is fundamental in tissue development and homeostasis1,2. While the role of cell proliferation in this process has been widely studied3, the mechanisms of organ size control and how it impacts cell fates remain elusive. Here, we use mouse blastocyst development as a model to unravel a key role of fluid-filled lumen in embryonic size control and cell fate specification. We find that during blastocyst expansion, there is a two-fold increase in the pressure of the lumen that translates into a concomitant increase in the cortical tension of trophectoderm (TE) cells lining the lumen. Increased cortical tension leads to vinculin mechanosensing and maturation of the functional tight junctions, thereby establishing a positive feedback loop to accommodate lumenal growth. However, when the cortical tension reaches a critical threshold, cell-cell adhesion cannot be sustained, and mitotic entry leads to a rupture of TE epithelium, fluid leakage and collapse of the blastocyst cavity. A simple theory of hydraulically-gated oscillations that integrates these feedback interactions recapitulates the evolution of cavity size and predicts the scaling of embryonic size with the tissue volume. Our theory further predicts that reduced cortical tension or disrupted tight junctions, and increased tissue stiffness lead to smaller embryonic size. These predictions are verified experimentally by embryological, pharmacological and genetic manipulations of the embryos. Remarkably, these changes to lumenal size, without a change in the tissue volume, lead to alteration of tissue architecture and cell fate. Overall, our study reveals how lumenal pressure and tissue mechanics control embryonic size at the tissue scale, that in turn couples to cell position and fate at the cellular scale.