Nervous System Regeneration: Molecular Mechanisms that Limit Axonal Regeneration Following Spinal Cord Injury, Optic Nerve Injury and Multiple Sclerosis. Diseases/Research Topics Nervous System Regeneration, Spinal Cord Injury, Optic Nerve Injury, Multiple Sclerosis, Axon Stability, Wallerian Degeneration, Axon Regeneration, Axon Growth, Axon Guidance, Synaptic Plasticity, Mouse Genetics. A long standing goal of our research is to understand how neuronal growth and sprouting is regulated in the mammalian nervous system during development, adult neuronal plasticity, and following injury(i.e. spinal cord injury, traumatic brain injury, stroke or multiple sclerosis). We pursue a mouse genetic approach to study the function of different classes of proteins that are known to regulate neuronal growth, including members of the Semaphorin family and their cognate receptors (Neuropilins and Plexins), and myelin-associated inhibitors/chondroitin sulfate proteoglycans and their receptors. The Nogo receptors NgR1 and NgR2, as well as paired immunoglobulin-like receptor B (PirB), have been implicated in regulating acute neuronal responses to the myelin inhibitors Nogo/RTN4, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). We are currently investigating the importance of these high-affinity receptors in mediating cell-type specific inhibition in vitro and in vivo, as well as the signaling pathways that are subsequently activated. We have also identified a novel function for NgR1 in regulating activity-dependent synaptic strength. Ongoing studies are aimed at understanding the mechanisms of how enhanced neuronal plasticity leads to improved functional outcomes following nervous system injury. In addition, we recently identified the Nogo receptors NgR1 and NgR3 as novel receptors for a second major group of growth inhibitors, the chondroitin sulfate proteoglycans (CSPGs). Thus, myelin inhibitors and CSPGs employ overlapping yet distinct members of the Nogo receptor family to signal neuronal growth inhibition. We are currently investigating the significance of this interaction in vitro and in vivo. A third line of investigation is focused on mechanisms of axon-glia interaction during nervous system development, adult homeostasis and disease. Myelin-associated glycoprotein (MAG) has an axon protective function in vivo; however, the mechanisms of MAG-mediated axon protection are poorly understood. We have identified the Nogo receptor family member NgR2 as a high-affinity receptor for MAG and we are currently investigating the role of NgR2 in MAG signaling in vivo.