TAK1 promotes BMP4/Smad1 signaling via inhibition of erk MAPK: A new link in the FGF/BMP regulatory network

• Published in: Differentiation (London) 2012-04, Vol.83 (4), p.210-219
• Main Authors: Liu, Chen, Goswami, Mousumi, Talley, Julia, Chesser-Martinez, Patricia L., Lou, Chih-Hong, Sater, Amy K.
• Format: Article
• Language: English
• Subjects: Animals; BMP; Bone Morphogenetic Protein 4 - metabolism; Down-Regulation; Embryo; erk MAP kinase; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Fibroblast Growth Factors - physiology; Immunohistochemistry; In Situ Hybridization; MAP Kinase Kinase Kinases - physiology; Real-Time Polymerase Chain Reaction; Signal Transduction; Smad1; Smad1 Protein - metabolism; TAK1; Xenopus; Xenopus - embryology; Xenopus Proteins - metabolism
• ISSN: 0301-4681; 1432-0436
• DOI: 10.1016/j.diff.2011.12.007

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. ► TAK1 inhibits activation of erk MAPK through p38-dependent inhibition of MEK. ► Downregulation of TAK1 leads to increased activation of MAPK in ectoderm and mesoderm. ► TAK1 maintains levels of nuclear Smad1 and Smad1-dependent gene expression. ► TAK1 functions to establish boundaries for organizer gene expression. ► TAK1 restricts the spatial extent of erk MAPK activation.