Axon growth inhibition: signals from the p75 neurotrophin receptor


435 Why do axons regenerate after injury in the peripheral but not the central nervous system (CNS)? Decades of work have established that much of the growth inhibition in the mammalian CNS is due to proteins in CNS myelin, which normally serves to insulate axons and facilitate fast electrical conductance along nerve fibers. Given that myelin proteins are centrally involved in suppressing axonal growth after spinal cord injury, identifying their inhibitory signaling mechanisms should provide pharmacological targets for the development of drugs to prevent their action and thereby promote spinal cord regeneration. In this issue, Yamashita and Tohyama1 identify one of the important signaling mechanisms used by myelin proteins and develop an agent that will disrupt their growth inhibitory actions. What is the nature of this signaling mechanism? Myelin contains three growth-inhibitory proteins—myelinassociated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (OMgp) and Nogo-A—and all three act by binding to a common target, the Nogo receptor (for review, see refs. 2,3). The Nogo receptor (NgR) mediates many of its inhibitory actions by interacting with the p75 neurotrophin receptor (p75NTR)4–6, which is best known for its ability to modulate the activity of the TrkA nerve growth factor (NGF) receptor and to induce apoptosis in neurons and oligodendrocytes. These previous studies show that NgR directly binds to the extracellular domain of p75NTR, but they do not define the relevant signaling mechanisms. Yamashita and Tohyama1 address this key point and identify p75NTR binding to the Rho guanine dissociation inhibitor When in the GTP-bound state, Rho interacts with a series of intracellular proteins that regulate the assembly and stability of the actin cytoskeleton and cytoskeletal plasticity7. Rho proteins are regulated either by enzymes that enhance GTP binding and activity (guanine nucleotide exchange factors or GEFs) or by proteins that increase the hydrolysis of GTP (GTPase activating proteins or GAPs) and thus decrease activity. Rho is kept in an inactive state in cells by Rho-GDIs8. Rho-GDIs exert their inhibitory function in three ways: first, by binding to and sequestering Rho news and views

DOI: 10.1038/nn0503-435
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@article{Kaplan2003AxonGI, title={Axon growth inhibition: signals from the p75 neurotrophin receptor}, author={David R Kaplan and F. D. Miller}, journal={Nature Neuroscience}, year={2003}, volume={6}, pages={435-436} }