Coucouvanis E, Martin G R
Department of Anatomy and Program in Developmental Biology, School of Medicine, University of California, San Francisco, CA 94143-0452, USA.
Development. 1999 Feb;126(3):535-46. doi: 10.1242/dev.126.3.535.
At E4.0 the inner cell mass of the mouse blastocyst consists of a core of embryonic ectoderm cells surrounded by an outer layer of primitive (extraembryonic) endoderm, which subsequently gives rise to both visceral endoderm and parietal endoderm. Shortly after blastocyst implantation, the solid mass of ectoderm cells is converted by a process known as cavitation into a pseudostratified columnar epithelium surrounding a central cavity. We have previously used two cell lines, which form embryoid bodies that do (PSA1) or do not (S2) cavitate, as an in vitro model system for studying the mechanism of cavitation in the early embryo. We provided evidence that cavitation is the result of both programmed cell death and selective cell survival, and that the process depends on signals from visceral endoderm (Coucouvanis, E. and Martin, G. R. (1995) Cell 83, 279-287). Here we show that Bmp2 and Bmp4 are expressed in PSA1 embryoid bodies and embryos at the stages when visceral endoderm differentiation and cavitation are occurring, and that blocking BMP signaling via expression of a transgene encoding a dominant negative mutant form of BMP receptor IB inhibits expression of the visceral endoderm marker, Hnf4, and prevents cavitation in PSA1 embryoid bodies. Furthermore, we show that addition of BMP protein to cultures of S2 embryoid bodies induces expression of Hnf4 and other visceral endoderm markers and also cavitation. Taken together, these data indicate that BMP signaling is both capable of promoting, and required for differentiation of, visceral endoderm and cavitation of embryoid bodies. Based on these and other data, we propose a model for the role of BMP signaling during peri-implantation stages of mouse embryo development.
在胚胎发育4.0天（E4.0）时，小鼠囊胚的内细胞团由一层胚胎外胚层细胞核心组成，其周围是一层原始（胚外）内胚层外层细胞，随后这层细胞会分化为脏壁内胚层和壁内胚层。囊胚着床后不久，外胚层细胞的实体团通过一种称为空泡化的过程转变为围绕中央腔的假复层柱状上皮。我们之前使用了两种细胞系，它们形成的类胚体有的会发生空泡化（PSA1），有的不会发生空泡化（S2），以此作为体外模型系统来研究早期胚胎空泡化的机制。我们提供的证据表明，空泡化是程序性细胞死亡和选择性细胞存活共同作用的结果，并且这个过程依赖于来自脏壁内胚层的信号（库库瓦尼斯，E.和马丁，G.R.（1995年）《细胞》83卷，279 - 287页）。在此我们表明，在脏壁内胚层分化和空泡化发生的阶段，Bmp2和Bmp4在PSA1类胚体和胚胎中表达，并且通过表达编码BMP受体IB显性负性突变形式的转基因来阻断BMP信号传导，会抑制脏壁内胚层标志物Hnf4的表达，并阻止PSA1类胚体发生空泡化。此外，我们还表明，向S2类胚体培养物中添加BMP蛋白会诱导Hnf4和其他脏壁内胚层标志物的表达，同时也会诱导空泡化。综合这些数据表明，BMP信号传导既能促进脏壁内胚层的分化和类胚体的空泡化，也是其分化所必需的。基于这些及其他数据，我们提出了一个关于BMP信号传导在小鼠胚胎发育着床前期阶段作用的模型。
