Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5001, USA.
Differentiation. 2012 Apr;83(4):210-9. doi: 10.1016/j.diff.2011.12.007. Epub 2012 Mar 2.
FGFs and BMPs act in concert to regulate a wide range of processes in vertebrate development. In most cases, FGFs and BMPs have opposing effects, and specific developmental outcomes arise out of a balance between the two growth factors. We and others have previously demonstrated that signaling pathways activated by FGFs and BMPs interact via inhibitory crosstalk. Here we demonstrate a role for the BMP effector TGF-β Activated Kinase 1 (TAK1) in the maintenance of Smad1 activity in Xenopus embryos, via the inhibition of erk MAPK. Up- or downregulation of TAK1 levels produces an inverse alteration in the amount of activated erk MAPK. The inhibition of erk MAPK by TAK1 is mediated by p38 and a corresponding decrease in phosphorylation of MEK. TAK1 morphant embryos show a decrease in the nuclear accumulation of Smad1. Conversely, reduction of erk MAPK activity via overexpression of MAP Kinase Phosphatase1 (MKP1) leads to an increase in nuclear Smad1. Both TAK1 morphant ectoderm and ectoderm treated with FGF show a decrease in the expression of several Smad1-inducible genes. Neural-specific gene expression is inhibited in isolated ectoderm coexpressing noggin and TAK1, suggesting that TAK1 is sufficient to inhibit neural specification. Introduction of TAK1 morpholino oligonucleotide expands the expression of organizer genes, disrupts formation of the boundary between organizer and non-organizer mesoderm, and increases the spatial range of MAPK activation in response to localized FGF. Our results indicate that inhibitory interactions between FGF and BMP4 effector pathways increase the robustness of BMP signaling via a feed-forward mechanism.
FGFs 和 BMPs 协同作用，调节脊椎动物发育过程中的多种过程。在大多数情况下，FGFs 和 BMPs 具有相反的作用，特定的发育结果是由两种生长因子之间的平衡产生的。我们和其他人以前已经证明，由 FGFs 和 BMPs 激活的信号通路通过抑制性串扰相互作用。在这里，我们证明了 BMP 效应物 TGF-β 激活激酶 1（TAK1）通过抑制 erk MAPK 在维持 Xenopus 胚胎中的 Smad1 活性中的作用，通过抑制 erk MAPK。TAK1 水平的上调或下调会导致激活的 erk MAPK 的量发生相反的改变。TAK1 通过 p38 和 MEK 相应磷酸化的降低来介导 erk MAPK 的抑制。TAK1 突变体胚胎显示 Smad1 的核积累减少。相反，通过过表达 MAP Kinase Phosphatase1（MKP1）降低 erk MAPK 活性会导致核 Smad1 增加。TAK1 突变体外胚层和用 FGF 处理的外胚层均显示出几种 Smad1 诱导基因的表达减少。在共表达 noggin 和 TAK1 的分离外胚层中，神经特异性基因表达受到抑制，表明 TAK1 足以抑制神经特化。引入 TAK1 突变体寡核苷酸会扩展组织者基因的表达，破坏组织者和非组织者中胚层之间的边界形成，并增加对局部 FGF 反应的 MAPK 激活的空间范围。我们的结果表明，FGF 和 BMP4 效应物途径之间的抑制性相互作用通过正反馈机制增加了 BMP 信号的稳健性。
