Smad Anchor for Receptor Activation (SARA) participation as a negative regulator of the TGFβ signaling pathway in neuronal development

ROZÉS SALVADOR V; SIRI SO; CONDE C

Workshop; 5th Edition of the EMBO Workshop, Emerging Concepts of the Neuronal Cytoskeleton; 2019

"Several events are necessary for proper neuronal development, such as cytoskeletal dynamics and endosomal trafficking. Smad Anchor for Receptor Activation (SARA) is a protein that binds to early endosomes; carrying out specific functions related to traffic but also participating in signaling such as TGFβ pathway. It has been described that SARA recruits Smad2/3 and, therefore, favors the activation of the pathway in epithelial cells. Moreover, it has been shown that TGFβ signaling specifies axon during neuronal development; however, SARA participation in this signaling pathway during the developmental process remains unknown. For this reason we proposed to analyze the role of SARA in the TGFβ signaling during neuronal development. Preliminary results in hippocampal neurons, through FRET Acceptor Photobleaching showed interaction between SARA and the TGFβ receptor. Also, performing loss and gain of function experiments, SARA supression (through shRNA expression) generates both greater axonal growth and loss of axonal specification since neurons have more than one axon compared with the control. Interestingly, this same phenotype is obtained when we use a mutant form of SARA that prevents its binding to PP1c protein and therefore, the TβRI remains hyperphosphorylated, keeping the pathway activated.These results suggest that SARA participates in TGFβ pathway in neurons through the n negative regulation, which seems to be a requirement for the correctneuronal development."