The signaling adaptor protein CD3ζ is a negative regulator of dendrite development in young neurons

A novel idea is emerging 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 CD3 zeta, 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 CD3 zeta is mainly expressed in neurons. Distribution of CD3 zeta in developing cultured hippocampal neurons, as determined by immunofluorescence, indicates that CD3 zeta is preferentially associated with the somatodendritic compartment as soon as the dendrites initiate their differentiation. At this stage, CD3 zeta was selectively concentrated at dendritic filopodia and growth cones, actin-rich structures involved in neurite growth and patterning. siRNA-mediated knockdown of CD3 zeta in cultured neurons or overexpression of a loss-of-function CD3 zeta mutant lacking the tyrosine phosphorylation sites in the immunoreceptor tyrosine-based activation motifs (ITAMs) increased dendritic arborization. Conversely, activation of endogenous CD3 zeta by a CD3 zeta antibody reduced the size of the dendritic arbor. Altogether, our findings reveal a novel role for CD3 zeta in the nervous system, suggesting its contribution to dendrite development through ITAM-based mechanisms.