MOLECULAR MECHANISM OF EARLY DEVELOPMENTAL PATTERNING BY TGF-B FACTORS

80年代末，S提出了多肽生长因子在早期发育调控中的重要作用。从那时起，发育生物学家对生长因子在胚胎成型中的作用进行了广泛的研究。利用非洲爪哇的研究表明，生长因子至少参与了两种诱导，细胞与细胞之间的相互作用控制着早期胚胎的发生。它们是中胚层诱导和神经诱导。在这个合作项目的过程中，我们已经证明了转化生长因子-β激活素和VGL超家族成员可以诱导背侧中胚层，如脊索和肌肉。另一种是骨形态发生蛋白(BMP)，可诱导腹侧中胚层，如血液。另一种诱导是神经诱导，由BMP调节。BMP似乎通过诱导表皮来抑制外胚层的神经诱导。我们提出了非洲爪哇外胚层注定成为无神经通道的模型，腹侧定位的BMP活性抑制了神经的命运。这一模型进一步表明，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folistatin是BMP结合蛋白，因此它是神经诱导剂。最后，我们还发现了在BMP调节途径中起作用的成分。它们包括acrtivin和BMP的受体，这两个受体都是丝氨酸/苏氨酸激酶，Smad，以及一种新的MAPKKK，TAKI。我们已经证明，它们在BMP下游的早期胚胎发育中也起着重要作用。特别是同源盒基因MSX-1被证明模仿BMP的作用：在Xogenopus的背裂球中过表达MSX-1使胚胎内腔。我们相信，我们在这一国际合作中的努力阐明了生长因子在调节早期发育中作用的分子机制的重要部分。

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.