Neurotrophin-3 stimulates neurogenetic proliferation via the extracellular signal-regulated kinase pathway.

The effects of neurotrophin-3 (NT3) administered into the ventricular space of 13.5-day-old mouse embryos on neurogenesis in the developing cerebral cortex were examined. 5-Bromo-2'-deoxyuridine (BrdU) was injected into pregnant mice 3 hr after the NT3 administration to label the neural progenitor cells. NT3 increased the number of BrdU-positive cells without altering their distribution. The increment in BrdU-positive cells 24 hr after the BrdU injection was attributed to Pax6-/BrdU-positive cells (neural stem cells), which was followed by a significant elevation of the number of Tuj1-/BrdU-positive cells (neurons) 36 or 48 hr after the BrdU injection, suggesting that NT3 facilitated neurogenesis by acting in two sequential steps, i.e., causing proliferation of neural stem cells and generation of neurons from these progenitors. NT3 stimulated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and ERK5 in the cortical progenitors, and the effects of NT3 on the increase in total BrdU-positive cells and Pax6-/BrdU-positive cells were diminished by an MEK inhibitor, suggesting the involvement of MEK-mediated ERK signal transduction in the NT3 actions.