Dominant-negative Smad2 mutants inhibit activin/Vg1 signaling and disrupt axis formation in Xenopus

Dev Biol. 1999 Mar 15;207(2):364-79. doi: 10.1006/dbio.1998.9168.

Abstract

Smads are central mediators of signal transduction for the TGFbeta superfamily. However, the precise functions of Smad-mediated signaling pathways in early development are unclear. Here we demonstrate a requirement for Smad2 signaling in dorsoanterior axis formation during Xenopus development. Using two point mutations of Smad2 previously identified in colorectal carcinomas, we show that Smad2 ushers Smad4 to the nucleus to form a transcriptional activation complex with the nuclear DNA-binding protein FAST-1 and that the mutant proteins interact normally with FAST-1 but fail to recruit Smad4 into the nucleus. This mechanism of inhibition specifically restricts the dominant-negative activity of these mutants to the activin/Vg1 signaling pathway without inhibiting BMPs. Furthermore, expression of these mutants in Xenopus animal caps inhibits but does not abolish activin and Vg1 induction of mesoderm and in the embryo results in a truncated dorsoanterior axis. These studies define a mechanism through which mutations in Smad2 may block TGFbeta-dependent signaling and suggest a critical role for inductive signaling mediated by the Smad2 pathway in Xenopus organizer function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I
  • Activins
  • Animals
  • COS Cells
  • DNA-Binding Proteins / genetics*
  • Embryonic Development
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Developmental / genetics
  • Inhibins / genetics*
  • Morphogenesis
  • Mutation
  • Nerve Growth Factors
  • Phosphorylation
  • RNA, Messenger / metabolism
  • Receptors, Growth Factor / genetics
  • Signal Transduction / genetics*
  • Smad Proteins
  • Smad2 Protein
  • Smad4 Protein
  • Trans-Activators / genetics*
  • Transcription Factors / genetics
  • Transcriptional Activation / genetics
  • Transfection
  • Transforming Growth Factor beta / genetics
  • Xenopus / embryology*
  • Xenopus Proteins*

Substances

  • DNA-Binding Proteins
  • FOXH1 protein, Xenopus
  • Forkhead Transcription Factors
  • Foxh1 protein, mouse
  • Nerve Growth Factors
  • RNA, Messenger
  • Receptors, Growth Factor
  • Smad Proteins
  • Smad2 Protein
  • Smad2 protein, Xenopus
  • Smad4 Protein
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Xenopus Proteins
  • smad4.1 protein, Xenopus
  • smad4.2 protein, Xenopus
  • Activins
  • Inhibins
  • Activin Receptors, Type I