Fine-Tuning the TGF beta Signaling Pathway by SARA During Neuronal Development

Abstract

Neural development is a complex process that involves critical events, including cytoskeleton dynamics and selective trafficking of proteins to defined cellular destinations. In this regard, Smad Anchor for Receptor Activation (SARA) is an early endosome resident protein, where perform trafficking- associated functions. In addition, SARA is also involved in cell signaling, including the TGF beta-dependent pathway. Accordingly, SARA, and TGF beta signaling are required for proper axonal specification and migration of cortical neurons, unveiling a critical role for neuronal development. However, the cooperative action between the TGF beta pathway and SARA to this process has remained understudied. In this work, we show novel evidence suggesting a cross-talk between SARA and TGF beta pathway needed for proper polarization, axonal specification, growth and cortical migration of central neurons bothin vitroandin vivo. Using microscopy tools and cultured hippocampal neurons, we show a local interaction between SARA and T beta RI (TGF beta I receptor) at endosomes. In addition, SARA loss of function, induced by the expression of the dominant-negative SARA-F728A, over-activates the TGF beta pathway, most likely by preserving phosphorylated T beta RI. Consequently, SARA-mediated activation of TGF beta pathway impacts on neuronal development, promoting axonal growth and cortical migration of neurons during brain development. Moreover, our data suggests that SARA basally prevents the activation of T beta RI through the recruitment of the inhibitory complex PP1c/GADD34 in polarizing neurons. Together, these results propose that SARA is a negative regulator of the TGF beta pathway, being critical for a proper orchestration for neuronal development.