Integrated β-catenin, BMP, PTEN, and Notch signalling patterns the nephron.
Integrated β-catenin, BMP, PTEN, and Notch signalling patterns the nephron.
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DOI：
10.7554/elife.04000
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发表时间：
2015-02-03
期刊：
影响因子：
7.7
通讯作者：
Hohenstein P
中科院分区：
文献类型：
--
作者：
Lindström NO;Lawrence ML;Burn SF;Johansson JA;Bakker ER;Ridgway RA;Chang CH;Karolak MJ;Oxburgh L;Headon DJ;Sansom OJ;Smits R;Davies JA;Hohenstein P
肾脏中肾单位和肾小球的不同部分平衡水稳态、溶质回收、血液过滤和代谢物排泄的过程。当节段功能被破坏时，会出现一系列病理特征。对胚胎发生过程中肾单位的形成知之甚少。在这项研究中，我们证明了早期肾单位是由β-连环蛋白活性梯度沿着轴的肾单位小管。通过改变β-连环蛋白活性，我们迫使肾单位内的细胞根据施加的β-连环蛋白活性水平分化，从而引起肾单位节段的空间移位。β-连环蛋白信号传导梯度与BMP途径相互作用，BMP途径通过PTEN/PI 3 K/AKT信号传导，拮抗β-连环蛋白活性并促进与低β-连环蛋白活性相关的片段身份。β-连环蛋白活性和PI 3 K信号传导也与Notch信号传导整合以控制节段：调节β-连环蛋白活性或PI 3 K挽救通常因抑制Notch而丢失的节段身份。因此，我们的数据确定了肾单位模式的分子网络。DOI：http://dx.doi.org/10.7554/eLife.04000.001肾脏的主要功能是过滤血液以清除废物并调节体内水和盐的量。肾脏中的结构称为肾单位，它完成了大部分的工作，血液在每个肾单位的一部分称为肾小球中过滤。从血液中过滤出来的物质进入一系列的“小管”，肾单位的另一部分，水和可溶性物质根据身体的需要被重新吸收或排出。如果肾单位不能正常工作，它会导致一系列的健康问题从不正常的水和盐的流失到危险的高血压。对于器官和组织在胚胎中发育，信号通路帮助细胞相互交流。这些通路控制胚胎细胞变成什么类型的细胞，也帮助相邻的细胞一起工作，形成具有特定功能的专门结构。关于肾单位如何发育，包括其不同结构如何协调它们的发育，以便它们在肾单位中的正确位置形成，还有很多未知数。已知一种称为β-连环蛋白的蛋白质在触发肾单位形成的最早阶段的信号通路中发挥重要作用。Lindström等人进一步研究了这种蛋白质如何通过使用广泛的技术来帮助肾单位发育，包括在培养物中培养基因改变的小鼠肾脏，以及用延时显微镜捕获发育中肾单位的图像。综合结果表明，β-连环蛋白活性水平协调肾单位中不同结构的发育。β-连环蛋白在肾单位的所有部分中的活性并不相等;相反，它形成不同活性水平的梯度。最高水平的β-连环蛋白活性发生在发育中的肾单位最远端的小管中;这种活性沿着肾单位的长度沿着逐渐降低，并且肾小球本身完全缺乏β-连环蛋白活性。实验性地操纵肾单位沿着不同点的β-连环蛋白水平，导致这些细胞具有错误的身份，导致肾单位的部分在错误的位置形成。Lindström等人还能够确定由β-连环蛋白活性控制的信号通路与其他三种众所周知的信号通路相互作用，作为控制肾单位发育的网络的一部分。需要更多的研究来找出首先激活β-连环蛋白的信号以及该信号来自肾脏的何处。肾小管中的特定细胞如何解释不同信号的确切活动，以赋予细胞在肾单位中该位置的特定身份，这也有待发现。更好地理解这些过程最终将有助于为肾衰竭患者建立新的肾脏。DOI：http://dx.doi.org/10.7554/eLife.04000.002网站
The different segments of the nephron and glomerulus in the kidney balance the processes of water homeostasis, solute recovery, blood filtration, and metabolite excretion. When segment function is disrupted, a range of pathological features are presented. Little is known about nephron patterning during embryogenesis. In this study, we demonstrate that the early nephron is patterned by a gradient in β-catenin activity along the axis of the nephron tubule. By modifying β-catenin activity, we force cells within nephrons to differentiate according to the imposed β-catenin activity level, thereby causing spatial shifts in nephron segments. The β-catenin signalling gradient interacts with the BMP pathway which, through PTEN/PI3K/AKT signalling, antagonises β-catenin activity and promotes segment identities associated with low β-catenin activity. β-catenin activity and PI3K signalling also integrate with Notch signalling to control segmentation: modulating β-catenin activity or PI3K rescues segment identities normally lost by inhibition of Notch. Our data therefore identifies a molecular network for nephron patterning. DOI: http://dx.doi.org/10.7554/eLife.04000.001 The main function of the kidney is to filter blood to remove waste and regulate the amount of water and salt in the body. Structures in the kidney—called nephrons—do much of this work and blood is filtered in a part of each nephron called the glomerulus. The substances filtered out of the blood move into a series of ‘tubules’, another part of the nephrons, from where water and soluble substances are reabsorbed or excreted as the body requires. If the nephrons do not work correctly, it can lead to a wide range of health problems—from abnormal water and salt loss to dangerously high blood pressure. For organs and tissues to develop in an embryo, signalling pathways help cells to communicate with each other. These pathways control what type of cells the embryonic cells become and also help neighbouring cells work together to form specialised structures with particular functions. Much is unknown about how the nephron develops, including how its different structures coordinate their development with each other so that they form in the right position in the nephron. A protein called beta-catenin was already known to play an important role in the signalling pathways that trigger the earliest stages of nephron formation. Lindström et al. further investigated how this protein helps the nephron to develop by using a wide range of techniques, including growing genetically altered mouse kidneys in culture and capturing images of the developing nephrons with time-lapse microscopy. The combined results reveal that the levels of beta-catenin activity coordinate the development of the different structures in the nephron. The beta-catenin protein is not equally active in all parts of the nephron; instead, it forms a gradient of different activity levels. The highest levels of beta-catenin activity occur in the tubules at the furthest end of the developing nephron; this activity gradually decreases along the length of the nephron, and the glomerulus itself lacks beta-catenin activity altogether. Experimentally manipulating the levels of beta-catenin at different points along the nephron caused those cells to take on the wrong identity, causing parts of the nephron to form in the wrong place. Lindström et al. were also able to establish that the signalling pathway controlled by beta-catenin activity interacts with three other well-known signalling pathways as part of a network that controls nephron development. More research is required to find out which signal activates beta-catenin in the first place and from where in the kidney this signal comes. It also remains to be discovered how a particular cell in the tubule interprets the exact activities of the different signals to give the cell its specific identity for that place in the nephron. A better understanding of these sorts of processes will eventually help build new kidneys for people with kidney failure. DOI: http://dx.doi.org/10.7554/eLife.04000.002