TY - JOUR T1 - TGFβ1 induces axonal outgrowth via ALK5/PKA/SMURF1-mediated degradation of RhoA and stabilization of PAR6 JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0104-20.2020 SP - ENEURO.0104-20.2020 AU - Julia Kaiser AU - Martina Maibach AU - Ester Piovesana AU - Iris Salpeter AU - Nora Escher AU - Yannick Ormen AU - Martin E. Schwab Y1 - 2020/09/04 UR - http://www.eneuro.org/content/early/2020/09/03/ENEURO.0104-20.2020.abstract N2 - TGFβ1 has repeatedly been associated with axonal regeneration and recovery after injury to the CNS. We found TGFβ1 up-regulated in the stroke-denervated mouse spinal cord after ischemic injury to the motor cortex as early as four days post injury (dpi) and persisting up to 28 dpi. Given the potential role of TGFβ1 in structural plasticity and functional recovery after stroke highlighted in several published studies, we investigated its downstream signaling in an in vitro model of neurite outgrowth. We found that in this model, TGFβ1 rescues neurite outgrowth under growth inhibitory conditions via the canonical TGFβR2/ALK5 signaling axis. Thereby, protein kinase A (PKA)-mediated phosphorylation of the E3 ubiquitin ligase SMURF1 induces a switch of its substrate preference from PAR6 to the Ras homologue A (RhoA), in this way enhancing outgrowth on the level of the cytoskeleton. This proposed mechanism of TGFβ1 signaling could underly the observed increase in structural plasticity after stroke in vivo as suggested by the temporal and spatial expression of TGFβ1. In accordance with previous publications, this study corroborates the potential of TGFβ1 and associated signaling cascades as a target for future therapeutic interventions to enhance structural plasticity and functional recovery for stroke patients.Significance statement This study addresses a mechanism for TGFβ1 to increase compensatory axonal sprouting and growth after cortical stroke, e.g. in the stroke-denervated cervical spinal cord, where it was previously implicated as a potential growth-inducer. The signaling pathway includes the canonical receptor components ALK5 and SMAD3 and a downstream modulation of the cytoskeleton via PKA/SMURF1 induced downregulation of RhoA and upregulation of PAR6. Defining the downstream signaling pathway through which TGFβ1 can induce neurite outgrowth may provide new clinical targets for future therapeutic interventions to increase compensatory sprouting, thus contributing to functional recovery. ER -