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

Abstract

J. Neurochem. (2011) 119, 708–722. Abstract 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.

Impaired Spatial Memory in Mice Lacking CD3ζ Is Associated with Altered NMDA and AMPA Receptors Signaling Independent of T-Cell Deficiency

“…؊/؊ mice In the CNS, CD3 is mostly expressed in neurons (Baudouin et al, 2008;Xu et al, 2010;Angibaud et al, 2011). In cortical cultured neurons from CD3 ϩ/ϩ mice, CD3 immunoreactivity is distributed in clusters mainly overlapping the glutamatergic synaptic marker PSD95, in agreement with previous data from rat hippocampal cultured neurons ( Fig.…”

Epigenetic biomarkers of T-cells in human glioma

“…We also considered the potential that glioma tissue displaying early neural features might ectopically express CD3Z, since it can be expressed in the rat during early neuronal development. 27 After comparing CD3Z expression among different gene expression classes of GBM within the TCGA database, we found no significant expression of CD3Z in any GBM tissue and no association with proneural expression signature.…”

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

“…In fact, B-Raf was initially described as a neuronal protein (72); only later was its expression and function in immune cells shown (19,20). In contrast, TCR's z chain and the downstream kinase ZAP70 were recently found to play a role in regulating neuronal development (73,74). The functional similarities of Kidins220 in neurons and T cells are striking, suggesting that neurons and T cells use similar mechanisms to interpret extracellular cues to mount appropriate responses.…”