Bradykinin promotes neuron-generating division of neural progenitor cells via ERK activation

Abstract

During brain development, cells proliferate, migrate and differentiate in highly accurate patterns. In this context, published results indicate bradykinin (BK) functions in neural fate determination, favoring neurogenesis and migration. However, underlying mechanisms of BK are yet to be explored. Our findings indicate a previously unidentified role of BK action in inducing neuron-generating division in vitro and in vivo, since BK lengthened the G1-phase of the neural progenitor cells (NPC) cycle and increased TIS21 (PC3/BTG2) expression in hippocampus from newborn mice. This role, triggered by activation of the kinin-B2 receptor, was conditioned by ERK activation. Moreover, immunohistochemistry analysis of hippocampal dentate gyrus showed that the percentage of Ki67+ cells markedly increased in BK-treated mice, and ERK inhibition affected this neurogenic response. The progress of neurogenesis depended on sustained ERK phosphorylation and resulted in MAPK translocation to the nucleus in NPCs and PC12 cells, changing expression of genes such as Hes1 and Ngn2. In agreement with the function of ERK in integrating signaling pathways, effects of BK in stimulating neurogenesis were reversed following removal of PKC-mediated sustained phosphorylation.