A multi-domain fragment of Nogo-A protein is a potent inhibitor of cortical axon regeneration via Nogo receptor 1

J Biol Chem. 2011 May 20;286(20):18026-36. doi: 10.1074/jbc.M110.208108. Epub 2011 Mar 24.

Abstract

Nogo-A limits axon regeneration and functional recovery after central nervous system injury in adult mammals. Three regions of Nogo-A (Nogo-A-24, Nogo-66, and Nogo-C39) interact with the neuronal Nogo-66 receptor 1 (NgR1). Nogo-66 also interacts with a structurally unrelated cell surface receptor, paired immunoglobulin-like receptor (PirB). We show here that the other two NgR1-interacting domains, Nogo-A-24 and Nogo-C39, also bind to PirB with high affinity. A purified 22-kDa protein containing all three NgR1- and PirB-interacting domains (Nogo-22) is a substantially more potent growth cone-collapsing molecule than Nogo-66 for chick dorsal root ganglion neurons and mature cortical neurons. Moreover, Nogo-22 inhibits axon regeneration of mature cortical neurons in vitro more potently than does Nogo-66. Although all three NgR1-interacting domains of Nogo-A also interact with PirB, expression of PirB in mature cortical cultures is nearly undetectable. Consistent with a relatively minor role for PirB in mature cortical neurons, Nogo-22 inhibition of axon regeneration is abolished by genetic deletion of NgR1. Thus, NgR1 is the predominant receptor for Nogo-22 in regenerating cortical neurons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism*
  • Chickens
  • Chlorocebus aethiops
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / metabolism
  • Humans
  • Mice
  • Myelin Proteins / genetics
  • Myelin Proteins / metabolism*
  • Nogo Proteins
  • Nogo Receptor 1
  • Protein Structure, Tertiary
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Regeneration / physiology*

Substances

  • GPI-Linked Proteins
  • Myelin Proteins
  • Nogo Proteins
  • Nogo Receptor 1
  • Pirb protein, mouse
  • RTN4 protein, human
  • RTN4R protein, human
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Rtn4 protein, mouse