McMahon J A, Takada S, Zimmerman L B, Fan C M, Harland R M, McMahon A P
Department of Molecular and Cellular Biology, The Biolabs, Harvard University, Cambridge, Massachusetts 02138, USA.amcmahon.biosun.harvar d.edu
Genes Dev. 1998 May 15;12(10):1438-52. doi: 10.1101/gad.12.10.1438.
Embryonic patterning in vertebrates is dependent upon the balance of inductive signals and their specific antagonists. We show that Noggin, which encodes a bone morphogenetic protein (BMP) antagonist expressed in the node, notochord, and dorsal somite, is required for normal mouse development. Although Noggin has been implicated in neural induction, examination of null mutants in the mouse indicates that Noggin is not essential for this process. However, Noggin is required for subsequent growth and patterning of the neural tube. Early BMP-dependent dorsal cell fates, the roof plate and neural crest, form in the absence of Noggin. However, there is a progressive loss of early, Sonic hedgehog (Shh)-dependent ventral cell fates despite the normal expression of Shh in the notochord. Further, somite differentiation is deficient in both muscle and sclerotomal precursors. Addition of BMP2 or BMP4 to paraxial mesoderm explants blocks Shh-mediated induction of Pax-1, a sclerotomal marker, whereas addition of Noggin is sufficient to induce Pax-1. Noggin and Shh induce Pax-1 synergistically. Use of protein kinase A stimulators blocks Shh-mediated induction of Pax-1, but not induction by Noggin, suggesting that induction is mediated by different pathways. Together these data demonstrate that inhibition of BMP signaling by axially secreted Noggin is an important requirement for normal patterning of the vertebrate neural tube and somite.
脊椎动物胚胎模式形成依赖于诱导信号及其特定拮抗剂之间的平衡。我们发现，头蛋白（Noggin）编码一种在节点、脊索和背侧体节中表达的骨形态发生蛋白（BMP）拮抗剂，是正常小鼠发育所必需的。尽管头蛋白与神经诱导有关，但对小鼠中该基因敲除突变体的研究表明，头蛋白对这一过程并非必不可少。然而，头蛋白对于神经管随后的生长和模式形成是必需的。在没有头蛋白的情况下，早期依赖BMP的背侧细胞命运，即顶板和神经嵴会形成。然而，尽管脊索中 Sonic hedgehog（Shh）正常表达，但早期依赖Shh的腹侧细胞命运却逐渐丧失。此外，体节分化在肌肉和硬骨前体细胞中均存在缺陷。向近轴中胚层外植体添加BMP2或BMP4会阻断Shh介导的硬骨标记物Pax-1的诱导，而添加头蛋白则足以诱导Pax-1。头蛋白和Shh协同诱导Pax-1。使用蛋白激酶A刺激剂会阻断Shh介导的Pax-1诱导，但不会阻断头蛋白的诱导，这表明诱导是由不同途径介导的。这些数据共同表明，轴向分泌的头蛋白对BMP信号的抑制是脊椎动物神经管和体节正常模式形成所必需的重要条件。
