S100A12 protein is a strong inducer of neurite outgrowth from primary hippocampal neurons

Several members of the S100 family of Ca2+ binding proteins are at present known to be secreted and to have extracellular activities. We have investig ated the neurite inducing potential of extracellularly added S100A12. Human recombinant S100A12 was found to dramatically induce neuritogenesis of hip pocampal cells isolated from 17 to 19 days old rat embryos. The response to S100A12 was dependent on the dose in a bell-shaped manner. A 10-fold incre ase in neurite outgrowth was observed upon treatment with S100A12 in concen trations between 0.1 and 2.0 muM already after 24 h. Exposure to S100A12 fo r only 15 min was enough to induce neuritogenesis when measured after 24 h, but to obtain a maximal response, S100A12 had to be present in the culture for at least 4 h. The response to S100A12 was abolished by inhibitors of p hospholipase C (PLC), protein kinase C (PKC), Ca2+ flux, Ca2+/calmodulin de pendent kinase II (CaMKII) or mitogen-activated protein kinase kinase (MEK) . Therefore, we suggest that extracellular S100A12 triggers intracellular s ignal transduction in neurons, involving the classical mitogen-activated pr otein (MAP) kinase pathway and a phospholipase C-generated second messenger pathway leading to an increase in intracellular Ca2+ and activation of PKC , ultimately resulting in neuronal differentiation.