SARA regulates TGFβ signalling during axonal development and regrowth of DRG neurons

BOURBOTTE ASENSIO JM; ROZÉS SALVADOR V; CONDE C

Workshop; 2023 IUBMB EMBO Workshop Emerging Concepts of the Neuronal Cytoskeleton; 2023

SARA (Smad Anchor for Receptor Activation) is a scaffold protein localized in the early endosomes(EEs) with trafficking and signaling functions. Transforming Growth Factor Beta (TGFβ) is one of thesignaling pathway in which SARA is involved. Recently, in central nervous system, we have identifiedSARA as a negative regulator of the TGFβ pathway. In this work, we focus on the biological role ofSARA and its potential association with the TGFβ pathway, during the development and regeneration of sensory neurons (peripheral nervous system). Our results shows that SARA and TβRI are endogenously expressed in embryonic dorsal root ganglion (DRG) neurons cultures. We found that SARA and TGFβ receptor type I interacts in the early endosomes (EEs) and the external addition of TGFβ potentiates this interaction. In addition, by loss-of-function experiments, SARA knockdown increases axonal development of embryonic DRGs. The same effect was observed with exogenous stimulation of the TGFβ pathway, together with an increase in the phosphorylation and nuclear translocation of Smad 2/3 proteins. During axonal regrowth of postnatal DRGs cultures, TGFβ treatment promotes both neurite elongation and branching and reduced growth cone size. TGFβ stimulation increases SARA expression along with the number and distribution of SARA endosomes both at the soma and axon level. Moreover, our preliminary results shows that the addition of TGFβ post-axotomy of DRG explants increase the number and length of axons. In summary, SARA regulates TGFβ signaling during axonal growth and regrowth of sensory neurons, key physiological processes in neurodevelopment.