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.
Highlights
Neuronal plasticity and structural remodelling are fundamental feature of the developing nervous system and plays an essential role during learning and injury-dependent remodelling and regeneration [1]
We described previously that a subtraction hybridization screen and degenerative PCR primer search led to the identification of the Plasticity Related Gene family (PRG) (Fig. 1 A) [11, 23, 24]
Values are given as mean ± SEM, * p
Summary
Neuronal plasticity and structural remodelling are fundamental feature of the developing nervous system and plays an essential role during learning and injury-dependent remodelling and regeneration [1]. Axons extend over long distances and form contacts with their target structure and facilitate www.aging‐us.com functional connections [2]. These neuronal connections become stabilized and restricted during maturation and secure proper functioning of the brain [1]. Several extracellular ligands account for the neurite growth inhibitory environment after maturation and injury [3] One such factor represents lysophosphatidic acid (LPA) which is a bioactive lipid borne from astrocytes and blood serum [4,5,6]. Recent landmark studies revealed that pharmacological and genetic interfering with Nogo/NgR function or LPA signaling promotes axonal regeneration and functional recovery after CNS injury [10, 11]
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