Modulation of semaphorin3A activity by p75 neurotrophin receptor influences peripheral axon patterning

Ayal Ben-Zvi, Liat Ben-Gigi, Hagit Klein, Oded Behar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


The p75 neurotrophin receptor (p75NTR) interacts with multiple ligands and coreceptors. It is thought to mediate myelin growth inhibition as part of the Nogo receptor complex, in addition to its other roles. Paradoxically, however, peripheral axons of p75ExonIII-/- mutant embryos are severely stunted. This inhibition of axon growth may be a result of neurite elongation defects in p75NTR mutant neurons. Here, we show that p75ExonIII-/- DRG neurons are hypersensitive to the repellent molecule Semaphorin3A (Sema3A). NGF modulates Sema3A activity equally well in both the p75NTR mutant and wild-type neurons, indicating that the hypersensitivity of p75NTR mutant neurons is probably not related to their NGF receptor activity. Neuropilin1 and p75NTR partially colocalize in DRG growth cones. After Sema3A stimulation, the degree of colocalization is dramatically increased, particularly in clusters associated with Sema3A receptor complex activation. Coimmunoprecipitation studies show that p75NTR interacts directly with the Sema3A receptors Neuropilin1 and PlexinA4. When coexpressed with both Neuropilin1 and PlexinA4, p75NTR reduces the interaction between these two receptor components. Finally, p75NTR/Sema3A double-mutant embryos show growth similar to that observed in Sema3A-null mice. These data indicate that p75NTR is an important functional modulator of Sema3A activity and that, in the absence of p75NTR, oversensitivity to Sema3A leads to severe reduction in sensory innervation. Our results also suggest that while inhibition of p75 NTR in CNS injury may enhance nerve regeneration resulting from the inhibition of myelin-associated protein, it may also inhibit nerve regeneration through its modulation of Sema3A.

Original languageAmerican English
Pages (from-to)13000-13011
Number of pages12
JournalJournal of Neuroscience
Issue number47
StatePublished - 21 Nov 2007


  • Axon guidance
  • DRG
  • Development
  • Dorsal root ganglion
  • Knock-out mice
  • NGF
  • Nerve growth factor
  • Regeneration


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