Dual R-Smads interplay in the regulation of vertebrate neurogenesis

Abstract

During neurogenesis, multiple regulatory networks integrate extracellular and intracellular signals to ensure proper final numbers for each neuronal subtype at the end of the developmental process. The Activin/TGF-β signaling cascade is one of the main players of neurogenesis in vertebrates, balancing proliferation and differentiation of neural stem cells by regulating gene expression via the R-Smads transcription factors. Despite their equivalent upstream activation mechanism, Smad2 and Smad3 functions can be redundant or opposite depending on the particular context of the cell. We demonstrate that R-Smad simultaneously cooperate and antagonize in the regulation of gene expression in the context of vertebrate neurogenesis. We propose a model where synergism and antagonism appear as a consequence of the competition between Smad2 and Smad3 to form the different transcriptionally active heterotrimers with Smad4. This dual interplay of R-Smads significantly modulates the role of TGF-β pathway in the balance between proliferation and differentiation in the developing vertebrate spinal cord.