MOLECULAR MECHANISM OF EARLY DEVELOPMENTAL PATTERNING BY TGF-B FACTORS

80年代末，人们提出多肽生长因子在早期发育中起着重要的调节作用。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。对非洲爪蟾的研究表明，生长因子至少参与两种诱导，细胞间相互作用控制早期胚胎发生。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TGF-b超家族成员激活和Vgl可以诱导背中胚层如脊索和肌肉。相反，TGF-b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。另一种诱导，神经诱导受bmp调控，bmp似乎通过诱导表皮抑制外胚层的神经诱导。我们提出了一个模型，认为非洲爪蟾外胚层是注定要成为自然的，除非神经命运受到腹侧BMP活性的抑制。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，因此它们可以作为神经诱导剂。最后，我们还确定了在BMP调控通路中起作用的成分。它们包括激活素和BMP的受体，这两种受体都是丝氨酸/苏氨酸激酶Smad和一种新的MAPKKK TAKI。我们已经证明它们在早期胚胎发生中也发挥重要作用，作为BMP的下游。特别是，同源盒基因Msx-1被证明模仿BMP的作用：在爪蟾的背卵裂球中，Msx-1的过表达使胚胎呈腹侧化。总之，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.