MOLECULAR MECHANISM OF EARLY DEVELOPMENTAL PATTERNING BY TGF-B FACTORS

在80年代后期，已经提出多肽生长因子在早期发育的调节中起重要作用。从那时起，发育生物学家对生长因子在胚胎发育中的作用进行了广泛的研究。使用非洲爪蟾的研究澄清了生长因子参与至少两种诱导，即控制早期胚胎发生的细胞间相互作用。它们是中胚层诱导和神经诱导。在这个合作项目的过程中，我们已经表明，TGF-β超家族成员激活素和Vgl可以诱导背中胚层，如脊索和肌肉。与此相反，TGF-β家族的另一个成员骨形态发生蛋白（BMP）被证明可以诱导腹侧中胚层如血液，而另一种诱导作用--神经诱导则被发现受到BMP的调控，BMP似乎通过诱导表皮来抑制外胚层的神经诱导。我们提出了一个模型，非洲爪蟾外胚层是注定要成为naural tunless神经命运是由腹侧定位的BMP活性抑制。这个模型进一步表明，神经命运是一种默认状态。最近的研究发现，BMP结合蛋白如noggin、chordin和follistatin都是BMP结合蛋白，因此它们是神经诱导剂。最后，我们还发现了在BMP通路中起作用的组分，它们包括acrtivin和BMP的受体，它们都是Ser/Thr激酶，Smad和一种新的MAPKKK，TAKI。我们已经表明，它们在BMP下游作用的早期胚胎发生中也起重要作用。特别是，同源框基因Msx-1被证明模拟BMP的作用：Msx-1在非洲爪蟾背侧卵裂球中的过表达使胚胎腹侧化。我们相信，我们在这项国际合作中的努力阐明了生长因子在早期发育调控中的重要分子机制。

In the late 80's, it has been proposed that polypeptide growth factors are playing essential roles in the regulation of early development. Since then extensive studies on the function of growth factors in the paterning of embryo have been carried out by developmental biologists. Studies using Xenopus laevis clarified that growth factors are involved in at least two inductions, cell-to-cell interactions controlling early embryogenesis. They are mesoderm induction and neural induction. During the course of this collaboration program, we have shown that members of TGF-b superfamily activin and Vgl can induce dorsal mesoderm such as notochord and muscle. In contrast another member of the TGF-b family, bone morphogenetic protein (BMP) was shown to induce ventral mesoderm such as blood.The other induction, neural induction was found to be regulated by BMP.BMP appears to inhibit neural induction of ectoderm by inducing epidermis. We proposed a model that Xenopus ectoderm is fated to become naural tunless the neural fate is inhibited by ventrally located BMP activity. This model further suggests that neural fate is a default state. Recent study identified BMP-binding proteins such as noggin, chordin, and follistatin to be BMP-binding poteins, which is therefore acting as neural inducers.Finally, we have also identified componets acting in the pathway regulated BMP.They include receptors for acrtivin and BMP,both of which are Ser/Thr kinases, Smad, and a novel MAPKKK,TAKI.We have shown that they also play important roles in early embryogenesis acting down stream of BMP.Particularly, homeobox gene Msx-1 was shown to mimick the action of BMP : over expression of Msx-1 in dorsal blastomeres of Xenopus ventralizes the embryo.Together, we believe our effort in this international collaboration clarified important part of moleauclr mechanism of growth factor function in the regulation of early development.