title: Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury.
abstract: 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. Here we investigated the role of the PRG family on axonal and filopodia outgrowth. Comparative analysis revealed the strongest outgrowth induced by PRG3 (LPPR1). During development, PRG3 is ubiquitously located at the tip of neuronal processes and at the plasma membrane and declines with age. In utero electroporation of PRG3 induced dendritic protrusions and accelerated spine formations in cortical pyramidal neurons. The neurite growth promoting activity of PRG3 requires RasGRF1 (RasGEF1/Cdc25) mediated downstream signaling. 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. Transgenic adult mice with constitutive PRG3 expression displayed strong axonal sprouting distal to a spinal cord lesion. Moreover, fostered PRG3 expression promoted complex motor-behavioral recovery compared to wild type controls as revealed in the Schnell swim test (SST). Thus, PRG3 emerges as a developmental RasGRF1-dependent conductor of filopodia formation and axonal growth enhancer. PRG3-induced neurites resist brain injury-associated outgrowth inhibitors and contribute to functional recovery after spinal cord lesions. Here, we provide evidence that PRG3 operates as an essential neuronal growth promoter in the nervous system. Maintaining PRG3 expression in aging brain may turn back the developmental clock for neuronal regeneration and plasticity.
authors.affiliation: Department of Neurosurgery, Charité - Universitätsmedizin Berlin, D-10115 Berlin, Germany.|Present address: Department of Physics, University of California at San Diego, La Jolla, California 92093 USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Broggini
authors.affiliation: Brain Research Institute, University of Zurich and ETHZ, CH-8057 Zurich, Switzerland.|Art+Science Consulting, Zurich, Switzerland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schnell
authors.affiliation: Translational Cell Biology and Neurooncology Lab, Department of Neurosurgery, University Medical School Erlangen, Friedrich Alexander University of Erlangen - Nürnberg (FAU), D-91054 Erlangen, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Ghoochani
authors.affiliation: Center for Microscopy and Image Analysis, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: José María
authors.initials: JM
authors.lastname: Mateos
authors.affiliation: Translational Cell Biology and Neurooncology Lab, Department of Neurosurgery, University Medical School Erlangen, Friedrich Alexander University of Erlangen - Nürnberg (FAU), D-91054 Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchfelder
authors.affiliation: Dr. Erler Kliniken Nürnberg, Nürnberg, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Wiendieck
authors.affiliation: Department of Anesthesiology, University Medical Center, Focus Program Translational Neuroscience (FTN) of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schäfer
authors.affiliation: Translational Cell Biology and Neurooncology Lab, Department of Neurosurgery, University Medical School Erlangen, Friedrich Alexander University of Erlangen - Nürnberg (FAU), D-91054 Erlangen, Germany.
authors.forename: Ilker Y
authors.initials: IY
authors.lastname: Eyupoglu
authors.affiliation: Translational Cell Biology and Neurooncology Lab, Department of Neurosurgery, University Medical School Erlangen, Friedrich Alexander University of Erlangen - Nürnberg (FAU), D-91054 Erlangen, Germany.|BiMECON Ent., Berlin, ; Germany.
authors.forename: Nicolai E
authors.initials: NE
authors.lastname: Savaskan
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism*
chemical_list: D010744:Phosphoric Monoester Hydrolases
keywords: axonal regeneration; myelin; neural cytoskeleton; plasticity; spinal cord injury: rehabilitation