MOLECULAR MECHANISM FOR NEURAL FROMATION BY BMP

假定的外胚层产生表皮或自然组织，在原肠胚形成期间决定其命运。由于Spemann和Mangold在20世纪20年代的实验表明，两栖动物的背唇植入寄主胚胎的腹侧后，可以用包括脑和眼睛在内的神经组织诱导第二体轴，因此认为神经组织是由胚胎背唇区域发出的因子诱导形成的。然而，最近对多肽生长因子功能的研究表明，基态不是表皮形成，而是神经形成。也就是说，除非外胚被BMP诱导成表皮，否则注定要成为神经组织。此外，最近的研究表明，神经诱导发生是因为BMP的活性被其结合蛋白如noggin和chordin抑制。在这项研究中，我们发现卵泡素（follistatin）最初被认为是一种激活素结合蛋白（activin-binding protein），能够与BMP结合。我们进一步证实了卵泡抑素与BMP之间的相互作用，发现复合物的解离非常快，这使得检测卵泡抑素与BMP之间的相互作用，发现复合物的解离非常快，这使得通过常规生化方法检测相互作用变得困难。BMP的信号是通过细胞表面丝氨酸/苏氨酸激酶受体和细胞内介质介导的。为了阐明BMP的胞内信号机制，我们筛选了BMP的信号分子和靶基因。我们首先在爪蟾中发现了一个新的MAPKKK TAK1作为BMP信号的中介。由于TAK1显性阴性（激酶阴性）的过度表达诱导神经命运，TAK1被认为是BMP信号的中介。我们发现一个家庭盒基因msx-1是对BMP-2和BMP-4有反应的直接早期基因。我们进一步证实，msx-1过表达导致表型类似于BMP的功能获得。我们的研究阐明了部分BMP信号通路在神经抑制中的作用。少

Presumptive ectoderm gives rise to epidermal or naural tissues and the fate determination is made during gastrulation. Since after the experiments by Spemann and Mangold in 1920's showing that dorsal lip of amphibian can induce secondary body axis with neural tissues including brain and eyes when implanted in ventral side of host embryo, neural tissues are believed to be formed upon the induction triggered by factors emanated from the dorsal lip region of the embryo. However, recent studies on the function of polupeptide growth factors revealed that not epiudemal but neural formation is the ground state. Namely, ectodem is fated to become neural tissue is formed unless it is induced to become epidemis by BMP.Furthemore, it has recently been shown that neural induction takes place because BMP activity is inhibited by its binding proteins such as noggin and chordin.In this study, we have shown that follistatin which was originally known as an activin-binding protein, is able to bind BMP … More Thus follistatin inhibits epidermal inducging activity of BMP thereby induces neural fate. We further confirmed that tyhe interaction between follistatin and BMP and found that the dissociation of the complex is very fast, which makes detection of the interaction between follistatin and BMP and found that the dissociation of the complex is very fast, which makes detection of the interaction by conventional biochemical way difficult. The signal of BMP is mediated through cell surface ser/thr kinase recepotrs and intracellular mediators. To clarify the intyracellular signaling mechanism of BMP,we have screened for signaling moleculeS and target gene of BMP.We first identified a novel MAPKKK TAK1 as a mediater of BMP signal in Xenopus.Because overexpression of a dominant negative (kinase negatuive) TAK1 induced neural fate, TAK1 was suggested to be a mediatoR of BMP signal. We identified a homebox gene msx-1 as an immediate early gene responding to BMP-2 and BMP-4. We further confirmed that msx-1 overexpression leads to the phenotype reminicent to gain-of function of BMP.Our study has clarified a part of BMP signaling in the pathway of neural inhibition. Less