PUBLICATION

Inhibitor-resistant type I receptors reveal specific requirements for TGF-beta signaling in vivo

Authors
Ho, D.M., Chan, J., Bayliss, P., and Whitman, M.
ID
ZDB-PUB-060517-16
Date
2006
Source
Developmental Biology   295(2): 730-742 (Journal)
Registered Authors
Bayliss, Peter, Chan, Joanne
Keywords
Nodal, Activin, TGFβ, Xenopus, Zebrafish, ALK, Mesoderm induction, Left–right patterning
MeSH Terms
  • Activin Receptors/metabolism*
  • Activin Receptors, Type I
  • Animals
  • Benzamides/pharmacology
  • Dioxoles/pharmacology
  • Embryo, Nonmammalian
  • Embryonic Development
  • Enzyme Inhibitors/pharmacology*
  • Ligands
  • Nodal Protein
  • Signal Transduction*
  • Smad2 Protein/metabolism
  • Transforming Growth Factor beta/metabolism*
  • Xenopus Proteins
  • Zebrafish Proteins
PubMed
16684517 Full text @ Dev. Biol.
Abstract
Activin/nodal-like TGF-beta superfamily ligands signal through the type I receptors Alk4, Alk5, and Alk7, and are responsible for mediating a number of essential processes in development. SB-431542, a chemical inhibitor of activin/nodal signaling, acts by specifically interfering with type I receptors. Here, we use inhibitor-resistant mutant receptors to examine the efficacy and specificity of SB-431542 in Xenopus and zebrafish embryos. Treatment with SB-431542 eliminates Smad2 phosphorylation in vivo and generates a phenotype very similar to those observed in genetic mutants in the nodal signaling pathway. Inhibitor-resistant Alk4 efficiently rescues Smad2 signaling, developmental phenotype, and marker gene expression after inhibitor treatment. This system was used to examine type I receptor specificity for several activin/nodal ligands. We find that Alk4 can efficiently rescue signaling by a wide range of ligands, while Alk7 can only weakly rescue signaling by the same ligands. In whole embryos, nodal signaling during gastrulation can be rescued with Alk4, but not Alk7, while Alk5 can only mediate signaling by ligands expressed later in development. The combination of the ALK inhibitor SB-431542 with inhibitor-resistant ALKs provides a powerful set of tools for examining nodal/activin signaling during embryogenesis.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping