Bone morphogenic protein signalling suppresses differentiation of pluripotent cells by maintaining expression of E-Cadherin.
Bone morphogenic protein signalling suppresses differentiation of pluripotent cells by maintaining expression of E-Cadherin.
复制标题
DOI：
10.7554/elife.01197
复制
发表时间：
2013-12-17
期刊：
影响因子：
7.7
通讯作者：
Lowell S
中科院分区：
文献类型：
--
作者：
Malaguti M;Nistor PA;Blin G;Pegg A;Zhou X;Lowell S
骨形态发生蛋白（BMP）信号转导有助于维持多能性，并有利于中胚层在分化后的神经命运，但BMP控制分化的机制还没有很好地理解。我们报告说，BMP调节分化阻断下调Cdh 1，一个事件，伴随着神经和中胚层分化的最早阶段。我们发现，Cdh 1的损失是一个限制性的要求分化的多能细胞，Cdh 1活性的实验抑制拯救BMP施加的块分化。我们进一步表明，BMP的行为之前，并独立于Cdh 1总理多能细胞中胚层分化，从而有助于加强对神经分化的阻滞。我们的结论是，分化不仅取决于暴露于适当的外在线索，但也对形态发生事件，控制接受这些分化线索，我们解释了如何一个关键的多能性信号，BMP，饲料到这个控制机制。DOI：http://dx.doi.org/10.7554/eLife.01197.001人体由大约200种不同类型的细胞组成，所有这些细胞都来自一个受精卵。随着胚胎的发育，它的细胞分裂并分化成不同的谱系。每个谱系中的细胞继续形成有限数量的细胞类型，这些细胞类型是制造特定组织所必需的。因此，在早期发育过程中，细胞从具有成为许多不同细胞类型潜力的“多能性”转变为致力于一种特定细胞谱系。控制这一过程涉及大量的信号蛋白和途径。一种这样的蛋白质是骨形态发生蛋白，简称BMP，它在胚胎发育中有许多不同的作用：例如，它阻止多能细胞变成神经组织，它还鼓励胚胎干细胞为早期胚胎的“中胚层”做出贡献（这将形成肌肉，结缔组织和一些血细胞）。这两种作用是如何联系在一起的，以及它们是否依赖于类似的信号通路，都是未知的。BMP也被认为会触发被称为“Id因子”的蛋白质的产生-这代表“分化抑制剂”。现在，Malaguti等人研究了BMP和Id因子在控制小鼠胚胎发育中的作用，并发现这些蛋白质需要第三种蛋白质的帮助才能阻止多能细胞转化为神经组织。第三种蛋白质称为E-Cadherin，通常帮助细胞粘附在其他细胞上。Malaguti等人表明，失去这种蛋白质会促使细胞成为神经或中胚层组织，并且在神经组织形成之前，E-Cadherin水平必须下降。Malaguti等人还表明，促进细胞成为中胚层的一部分需要BMP激活另一条途径，而这条途径不需要E-钙粘蛋白。BMP的两种作用可以通过调节这种蛋白质的水平来解偶联。在低浓度下，BMP可以保持细胞的多能性，但它不能鼓励细胞致力于中胚层命运。然而，在更高的剂量下，BMP“启动”细胞对触发它们发育成中胚层组织的信号做出反应。Malaguti等人的研究结果表明，操纵E-Cadherin和BMP信号可以提高我们从实验室培养的干细胞中产生有用细胞类型（如神经元）的能力。DOI：http://dx.doi.org/10.7554/eLife.01197.002网站
Bone morphogenic protein (BMP) signalling contributes towards maintenance of pluripotency and favours mesodermal over neural fates upon differentiation, but the mechanisms by which BMP controls differentiation are not well understood. We report that BMP regulates differentiation by blocking downregulation of Cdh1, an event that accompanies the earliest stages of neural and mesodermal differentiation. We find that loss of Cdh1 is a limiting requirement for differentiation of pluripotent cells, and that experimental suppression of Cdh1 activity rescues the BMP-imposed block to differentiation. We further show that BMP acts prior to and independently of Cdh1 to prime pluripotent cells for mesoderm differentiation, thus helping to reinforce the block to neural differentiation. We conclude that differentiation depends not only on exposure to appropriate extrinsic cues but also on morphogenetic events that control receptivity to those differentiation cues, and we explain how a key pluripotency signal, BMP, feeds into this control mechanism. DOI: http://dx.doi.org/10.7554/eLife.01197.001 The human body is made up of about 200 different types of cell, all of which are descended from a single fertilised egg. As an embryo develops, its cells divide and specialise into distinct lineages. Cells in each lineage go on to form a restricted number of cell types that are required to make a specific tissue. As such, during early development, cells switch from being ‘pluripotent’, with the potential to become the many different cell types, to committing to one particular cell lineage. Controlling this process involves a huge number of signalling proteins and pathways. One such protein is bone morphogenetic protein, or BMP for short, which has a number of different roles in embryo development: for example, it stops pluripotent cells turning into nerve tissue, and it also encourages embryonic stem cells to contribute to the ‘mesoderm’ of the early embryo (which goes on to form the muscles, connective tissues and some blood cells). How these two actions are linked, and whether they depend on similar signalling pathways, was unknown. BMP is also known to trigger the production of proteins known as ‘Id factors’—which stands for ‘inhibitor of differentiation’. Now, Malaguti et al. have investigated the roles of BMP and Id factors in controlling mouse embryo development and found, somewhat surprisingly, that these proteins needed help from a third protein to stop pluripotent cells turning into nerve tissue. This third protein, which is called E-Cadherin, normally helps cells to adhere to other cells. Malaguti et al. showed that losing this protein encourages cells to become either nerve or mesoderm tissues, and that a drop in E-Cadherin levels must occur before nerve tissue can form. Malaguti et al. also showed that encouraging cells to become part of the mesoderm requires BMP to activate another pathway, which does not require E-Cadherin. The two effects of BMP can be uncoupled by adjusting the levels of this protein. At low concentrations, BMP can keep cells pluripotent, but it cannot encourage cells to commit to a mesoderm fate. At higher doses, however, BMP ‘primes’ cells to respond to the signals that trigger their development into mesoderm tissue. The findings of Malaguti et al. suggest that manipulating both E-Cadherin and BMP signalling could improve our ability to generate useful cell types, such as neurons, from stem cells grown in laboratory cultures. DOI: http://dx.doi.org/10.7554/eLife.01197.002