PRG3 Promotes Neural Regeneration

Researchers here identify a protein that increases regeneration in the central nervous system following injury, or to restore lost plasticity and ability to adapt in later life. Spurring greater regrowth of damaged nerves is of great interest to the research community, and a range of approaches are underway at various stages of development. Despite promising results in animal studies so far the practical outcomes for human medicine are all fairly marginal, however. This will change in the years ahead, but at this point it is hard to say just where or when, or which of the avenues will prove to be the first one that works well enough to follow through to widespread clinical availability.

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. In development, axons extend over long distances and form contacts with their target structure and facilitate functional connections. These neuronal connections become stabilized and restricted during maturation and secure proper functioning of the brain. 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.

Several extracellular ligands account for the neurite growth inhibitory environment after maturation and injury. These ligands converge on the RhoA-Rho kinase pathway mediating the final signal transduction for neurite retraction and axon growth inhibition. Pharmacological and genetic interfering with the ligands Nogo/NgR or LPA promotes axonal regeneration and functional recovery after central nervous system injury. An essential step during development and regeneration is the initiation of actin-rich membrane protrusions termed filopodia or microspikes. These structures are involved in cell attachment, migration and neurite growth. Filopodia initiation and neural growth depends on cytoskeletal dynamics regulated to a large extent by the small molecular weight GTPases of the Rho family. Here, we describe the individual morphogenic activity of the integral membrane proteins Plasticity Related Genes also termed Lipid Phosphate Phosphatases Related genes (PRG 1-5 or LPPR 1-5). They are differentially expressed in the developing brain and re-expressed in regenerating axons after a lesion. In particular, PRG3 induces the formation of filopodia and promotes axonal growth. The sequence of PRG3 is highly related to PRG5 which also promotes morphological changes in neurons. However, our comparative analysis revealed a hierarchy with PRG3 displaying the strongest outgrowth promoting activity among the entire PRG family.

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.



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