A novel idea is emergxsing that a large molecular repertoire is common to the nervous and immune systems, which might reflect the existence of novel neuronal functions for immune molecules in the brain. Here, we show that the transmembrane adaptor signaling protein CD3ζ, first described in the immune system, has a previously uncharacterized role in regulating neuronal development. Biochemical and immunohistochemical analyses of the rat brain and cultured neurons showed that CD3ζ is mainly expressed in neurons. Distribution of CD3ζ in developing cultured hippocampal neurons, as determined by immunofluorescence, indicates that CD3ζ is preferentially associated with the somatodendritic compartment as soon as the dendrites initiate their differentiation. At this stage, CD3ζ was selectively concentrated at dendritic filopodia and growth cones, actin-rich structures involved in neurite growth and patterning. siRNA-mediated knockdown of CD3ζ in cultured neurons or overexpression of a loss-of-function CD3ζ mutant lacking the tyrosine phosphorylation sites in the immunoreceptor tyrosine-based activation motifs (ITAMs) increased dendritic arborization. Conversely, activation of endogenous CD3ζ by a CD3ζ antibody reduced the size of the dendritic arbor. Altogether, our findings reveal a novel role for CD3ζ in the nervous system, suggesting its contribution to dendrite development through ITAM-based mechanisms
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