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Smad2 and Smad3 cooperate and antagonize simultaneously in vertebrate neurogenesis
David G Míguez1, Estel Gil-Guiñón, Sebastián Pons
1Instituto de Biología Molecular de Barcelona, CSIC, C/Baldiri i Reixac 20, Barcelona 08028, Spain.
Abstract:
The transforming growth factor beta (TGF-β) pathway plays key roles in development and cancer. TGF-β signaling converges on the Smad2 and Smad3 effectors, which can either cooperate or antagonize to regulate their transcriptional targets. Here we performed in vivo and in silico experiments to study how such cooperativity and antagonism might function during neurogenesis. In vivo electroporation experiments in the chick embryo neural tube show that Smad2 and Smad3 cooperate to promote neurogenesis, as well as the transcription of Smad3-specific targets. Knockdown of Smad2 enhances neurogenesis and the transcription of Smad3-specific targets. A mathematical model of the TGF-β pathway fits the experimental results and predicts that the proportions of the three different trimeric complexes formed dictates the transcriptional responses of the R-Smad proteins. As such, Smad2 targets are activated solely by the Smad2-Smad2-Smad4 complex, whereas Smad3 targets are activated both by Smad2-Smad3-Smad4 and Smad3-Smad3-Smad4 trimers. We have modeled the Smad responses onto arbitrary genes and propose that this mechanism might be extended to additional activities of TGF-β in development and disease.
Insights
Transforming growth factor beta (TGF-β) signaling in neurogenesis involves Smad2 and Smad3 proteins. Their complex interactions, detailed by a mathematical model, dictate gene transcription and neuronal development.
Area of Science:
- Molecular Biology
- Developmental Biology
- Systems Biology
Background:
- The transforming growth factor beta (TGF-β) pathway is crucial for development and cancer.
- TGF-β signaling involves Smad2 and Smad3 proteins, which exhibit cooperative and antagonistic interactions.
- Understanding these interactions is key to deciphering their roles in cellular processes like neurogenesis.
Purpose of the Study:
- To investigate the cooperative and antagonistic roles of Smad2 and Smad3 in neurogenesis.
- To elucidate the molecular mechanisms underlying Smad-mediated transcriptional regulation in the neural tube.
- To develop a predictive model for TGF-β pathway responses.
Main Methods:
- In vivo electroporation experiments in chick embryo neural tubes.
- Knockdown experiments to assess the function of Smad2 and Smad3.
- In silico mathematical modeling of the TGF-β pathway and Smad complex formation.
Main Results:
- Smad2 and Smad3 were found to cooperate in promoting neurogenesis and the transcription of Smad3-specific targets.
- Smad2 knockdown enhanced neurogenesis and the transcription of Smad3-specific targets.
- A mathematical model accurately predicted these findings, revealing that the proportions of Smad trimers (Smad2-Smad2-Smad4, Smad2-Smad3-Smad4, Smad3-Smad3-Smad4) determine target gene activation.
Conclusions:
- The specific composition of R-Smad trimers dictates transcriptional outcomes in the TGF-β pathway.
- Smad2-specific targets are activated by Smad2-Smad2-Smad4, while Smad3 targets are activated by both Smad2-Smad3-Smad4 and Smad3-Smad3-Smad4 complexes.
- This mechanism provides a framework for understanding TGF-β's diverse roles in development and disease.
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