Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein

Adult mammalian axon regeneration is generally successful in the peripheral nervous system (PNS) but is dismally poor in the central nervous system (C NS), However, many classes of CNS axons can extend for long distances in pe ripheral nerve grafts(1). A comparison of myelin from the CNS and the PNS h as revealed that CNS white matter is selectively inhibitory for axonal outg rowth(2). Several components of CNS white matter, NI35, NI250(Nogo) and MAG , that have inhibitory activity for axon extension have been described(3-7) The IN-1 antibody, which recognizes NI35 and NI250(Nogo), allows moderate degrees of axonal regeneration and functional recovery after spinal cord in jury(8,9). Here we identify Nogo as a member of the Reticulon family, Retic ulon 4-A. Nogo is expressed by oligodendrocytes but not by Schwann cells, a nd associates primarily with the endoplasmic reticulum. A 66-residue lumena l/extracellular domain inhibits axonal extension and collapses dorsal root ganglion growth cones. In contrast to Nogo, Reticulon 1 and 3 ape not expre ssed by oligodendrocytes, and the 66-residue lumenal/extracellular domains from Reticulon 1, 2 and 3 do not inhibit axonal regeneration. These data pr ovide a molecular basis to assess the contribution of Nogo to the failure o f axonal regeneration in the adult CNS.