Neural cell adhesion molecule 2 promotes the formation of filopodia and neurite branching by inducing submembrane increases in Ca2+ levels.

Changes in expression of the neural cell adhesion molecule 2 (NCAM2) have been proposed to contribute to neurodevelopmental disorders in humans. The role of NCAM2 in neuronal differentiation remains, however, poorly understood. Using genetically encoded Ca(2+) reporters, we show that clustering of NCAM2 at the cell surface of mouse cortical neurons induces submembrane [Ca(2+)] spikes, which depend on the L-type voltage-dependent Ca(2+) channels (VDCCs) and require activation of the protein tyrosine kinase c-Src. We also demonstrate that clustering of NCAM2 induces L-type VDCC- and c-Src-dependent activation of CaMKII. NCAM2-dependent submembrane [Ca(2+)] spikes colocalize with the bases of filopodia. NCAM2 activation increases the density of filopodia along neurites and neurite branching and outgrowth in an L-type VDCC-, c-Src-, and CaMKII-dependent manner. Our results therefore indicate that NCAM2 promotes the formation of filopodia and neurite branching by inducing Ca(2+) influx and CaMKII activation. Changes in NCAM2 expression in Down syndrome and autistic patients may therefore contribute to abnormal neurite branching observed in these disorders.