The immune molecule CD3zeta and its downstream effectors ZAP-70/Syk mediate ephrin signaling in neurons to regulate early neuritogenesis

J Neurochem. 2011 Nov;119(4):708-22. doi: 10.1111/j.1471-4159.2011.07469.x. Epub 2011 Oct 3.


Recent studies have highlighted the key role of the immune protein CD3ζ in the maturation of neuronal circuits in the CNS. Yet, the upstream signals that might recruit and activate CD3ζ in neurons are still unknown. In this study, we show that CD3ζ functions early in neuronal development and we identify ephrinA1-dependent EphA4 receptor activation as an upstream regulator of CD3ζ. When newly born neurons are still spherical, before neurite extension, we found a transient CD3ζ aggregation at the cell periphery matching the initiation site of the future neurite. This accumulation of CD3ζ correlated with a stimulatory effect on filopodia extension via a Rho-GEF Vav2 pathway and a repression of neurite outgrowth. Conversely, cultured neurons lacking CD3ζ isolated from CD3ζ(-/-) mice showed a decreased number of filopodia and an enhanced neurite number. Stimulation with ephrinA1 induces the translocation of both CD3ζ and its activated effector molecules, ZAP-70/Syk tyrosine kinases, to EphA4 receptor clusters. EphrinA1-induced growth cone collapse was abrogated in CD3ζ(-/-) neurons and was markedly reduced by ZAP-70/Syk inhibition. Moreover, ephrinA1-induced ZAP-70/Syk activation was inhibited in CD3ζ(-/-) neurons. Altogether, our data suggest that CD3ζ mediates the ZAP-70/Syk kinase activation triggered by ephrinA-activated pathway to regulate early neuronal morphogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Brain / cytology
  • CD3 Complex / genetics
  • CD3 Complex / metabolism*
  • COS Cells
  • Cells, Cultured
  • Chlorocebus aethiops
  • Embryo, Mammalian
  • Ephrins / genetics
  • Ephrins / metabolism*
  • Ephrins / pharmacology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Immunoprecipitation / methods
  • Mice
  • Mice, Knockout
  • Neural Stem Cells
  • Neurites / physiology*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • Pseudopodia / drug effects
  • Pseudopodia / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Time Factors
  • Transfection / methods
  • Tubulin / metabolism
  • ZAP-70 Protein-Tyrosine Kinase / genetics
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*


  • CD3 Complex
  • CD3 antigen, zeta chain
  • Ephrins
  • Tubulin
  • beta3 tubulin, mouse
  • Green Fluorescent Proteins
  • ZAP-70 Protein-Tyrosine Kinase