Overcoming inhibitors in myelin to promote axonal regeneration.
The lack of axonal growth after injury in the adult central nervous system (CNS) is due to several factors including the formation of a glial scar, the absence of neurotrophic factors, the presence of growth-inhibitory molecules associated with myelin and the intrinsic growth-state of the neurons. To date, three inhibitors have been identified in myelin: Myelin-Associated Glycoprotein (MAG), Nogo-A, and Oligodendrocyte-Myelin glycoprotein (OMgp). In previous studies we reported that MAG inhibits axonal regeneration by high affinity interaction (K(D) 8 nM) with the Nogo66 receptor (NgR) and activation of a p75 neurotrophin receptor (p75NTR)-mediated signaling pathway. Similar to other axon guidance molecules, MAG is bifunctional. When cultured on MAG-expressing cells, dorsal root ganglia neurons (DRG) older than post-natal day 4 (PND4) extend neurites 50% shorter on average than when cultured on control cells. In contrast, MAG promotes neurite outgrowth from DRG neurons from animals younger than PND4. The response switch, which is also seen in retinal ganglia (RGC) and Raphe nucleus neurons, is concomitant with a developmental decrease in the endogenous neuronal cAMP levels. We report that artificially increasing cAMP levels in older neurons can alter their growth-state and induce axonal growth in the presence of myelin-associated inhibitors.
Domeniconi
Marco
M
Hunter College of City University of New York, Department of Biological Sciences, 695 Park Avenue Room 807N, New York, NY 10021, USA.
Filbin
Marie T
MT
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D004347:Drug Interactions; D006133:Growth Substances / Q000494:pharmacology; D009185:Myelin Proteins / Q000378:metabolism* / Q000494:pharmacology; D009186:Myelin Sheath / Q000502:physiology*; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D006133:Growth Substances; D009185:Myelin Proteins