Elucidating the Role of Plasticity-Related Gene Type 3 Protein in the Central Nervous System
Agbaegbu Iweka, Chinyere Anne
Geller, Herbert M
Burns, Mark P
PRG-3 (Plasticity-Related Gene), a member of a family of lipid phosphatase related proteins, also known as Phospholipid Phosphatase-Related Protein Type (PLPPR) proteins, are integral membrane proteins characterized by six transmembrane domains. This family of proteins is enriched in the brain, and recent data indicate potential pleotropic functions in several different contexts. An inherent ability of this family of proteins is to promote the formation of membrane protrusions, and we have previously reported a cooperative function between the members of this family to induce membrane protrusions. PRG-3 was identified in a phospho-proteomic screen of proteins whose phosphorylation state was altered in response to Chondroitin Sulfate Proteoglycans (CSPGs), a robust inhibitor of axon growth. However, the function of PRG-3 is not yet understood. Here, we report that exogenous expression of PRG-3 increases cell adhesion to the ECM substrate resulting in decreased cell migration by altering cytoskeletal dynamics and modulating RhoA and Rac1 activity through association with RhoGDI, thus, enabling PRG-3 to overcome the inhibitory activity of CSPGs and LPA, another negative regulator of axon growth. We also show that deletion of PRG-3 resulted in the dilation of the lateral ventricles and increased dendritic spine density resulting in profound behavioral phenotypes. The PRG-3 knock-out mice exhibit general anxiety and hypoactivity, impaired prepulse inhibition and deficits in contextual learning and memory. Altogether, the data presented here suggest that PRG-3 may play a role in maintaining LPA levels in the brain parenchyma and may influence dendritic spine formation, maturation or pruning. Additionally, these results establish a novel signaling pathway for PRG-3 protein and by studying PRG-3 and its role in influencing cytoskeletal changes, we are reinforcing the significance of the factors and molecular mechanisms that govern axon growth after injury.
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