Fine-Tuning the TGF? 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?-dependent pathway. Accordingly, SARA, and TGF? 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? pathway and SARA to this process has remained understudied. In this work, we show novel evidence suggesting a cross-talk between SARA and TGF? pathway needed for proper polarization, axonal specification, growth and cortical migration of central neurons both in vitro and in vivo. Using microscopy tools and cultured hippocampal neurons, we show a local interaction between SARA and T?RI (TGF? I receptor) at endosomes. In addition, SARA loss of function, induced by the expression of the dominant-negative SARA-F728A, over-activates the TGF? pathway, most likely by preserving phosphorylated T?RI. Consequently, SARA-mediated activation of TGF? 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?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? pathway, being critical for a proper orchestration for neuronal development.

SUBMITTER: Rozes-Salvador V 

PROVIDER: S-EPMC7494740 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature