Ectopic Expression of the Immune Adaptor Protein CD3zeta in Neural Stem/Progenitor Cells Disrupts Cell-Fate Specification

Immune signaling and neuroinflammatory mediators have recently emerged as influential variables that regulate neural precursor/stem cell (NPC) behavior and function. In this study, we investigated whether the signaling adaptor protein CD3 zeta, a transmembrane protein involved in T cell differentiation and function and recently shown to regulate neuronal development in the central nervous system (CNS), may have a role in NPC differentiation. We analyzed the expression profile of CD3 zeta in embryonic rat brain during neurogenic periods and in neurosphere-derived neural cells, and we investigated the action of CD3 zeta on cell differentiation. We found that CD3 zeta expression coincided with neuronal commitment, but its forced expression in NPCs prevented the production of neurons and oligodendrocytes, but not astroglial cells. This blockade of neuronal differentiation was operated through an ITAM-independent mechanism, but required the Asp36 of the CD3 zeta transmembrane domain involved in membrane receptor interaction. Together, our findings show that ectopic CD3 zeta expression in NPCs impaired their normal cell-fate specification and suggest that variations of CD3 zeta expression in the developing CNS might result in neurodevelopmental anomalies.