Another blood inherent factor with neural shape forming activity is thrombin and its receptor-activating peptide domain (TRP). One such factor represents lysophosphatidic acid (LPA) which is a bioactive lipid borne from astrocytes and blood serum. Several extracellular ligands account for the neurite growth inhibitory environment after maturation and injury. Conversely, sprouting and regeneration is limited after decline of intrinsic axonal remodelling activity in aging brain and in an microenvironment rich in neurite growth inhibitors after neurological injury. These neuronal connections become stabilized and restricted during maturation and secure proper functioning of the brain. In development, axons extend over long distances and form contacts with their target structure and facilitate functional connections. Neuronal plasticity and structural remodelling are fundamental feature of the developing nervous system and plays also an essential role during learning and injury-dependent remodelling and regeneration. Maintaining PRG3 expression in aging brain may turn back the developmental clock for neuronal regeneration and plasticity. Here, we provide evidence that PRG3 operates as an essential neuronal growth promoter in the nervous system. PRG3-induced neurites resist brain injury-associated outgrowth inhibitors and contribute to functional recovery after spinal cord lesions. Thus, PRG3 emerges as a developmental RasGRF1-dependent conductor of filopodia formation and axonal growth enhancer. Moreover, fostered PRG3 expression promoted complex motor-behavioral recovery compared to wild type controls as revealed in the Schnell swim test (SST). Transgenic adult mice with constitutive PRG3 expression displayed strong axonal sprouting distal to a spinal cord lesion. Moreover, in axon collapse assays, PRG3-induced neurites resisted growth inhibitors such as myelin, Nogo-A (Reticulon/RTN-4), thrombin and LPA and impeded the RhoA-Rock-PIP5K induced neurite repulsion. The neurite growth promoting activity of PRG3 requires RasGRF1 (RasGEF1/Cdc25) mediated downstream signaling. In utero electroporation of PRG3 induced dendritic protrusions and accelerated spine formations in cortical pyramidal neurons. During development, PRG3 is ubiquitously located at the tip of neuronal processes and at the plasma membrane and declines with age. Comparative analysis revealed the strongest outgrowth induced by PRG3 (LPPR1). Here we investigated the role of the PRG family on axonal and filopodia outgrowth. The Plasticity Related Gene family covers five, brain-specific, transmembrane proteins (PRG1-5, also termed LPPR1-5) that operate in neuronal plasticity during development, aging and brain trauma. Received: JAccepted: SeptemPublished: Octo
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9 Present address: Department of Physics, University of California at San Diego, La Jolla, California 92093 USA.Erler Kliniken Nürnberg, Nürnberg, Germany 6 Department of Anesthesiology, University Medical Center, Focus Program Translational Neuroscience (FTN) of the Johannes Gutenberg-University Mainz, Germany.5 Center for Microscopy and Image Analysis, University of Zurich, CH-8057 Zurich, Switzerland.4 Translational Cell Biology and Neurooncology Lab, Department of Neurosurgery, University Medical School Erlangen, Friedrich Alexander University of Erlangen – Nürnberg (FAU), D-91054 Erlangen, Germany.3 Art+Science Consulting, Zurich, Switzerland.2 Brain Research Institute, University of Zurich and ETHZ, CH-8057 Zurich, Switzerland.1 Department of Neurosurgery, Charité - Universitätsmedizin Berlin, D-10115 Berlin, Germany.Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury