Neurotrophic activity of proNGF in vivo

Ectopic expression of nerve growth factor (NGF) in transgenic mice results in the directional growth of sympathetic and/or sensory fibers. For instance, mice that over-express NGF under the control of the glial fibrillary acidic protein (GFAP) promoter exhibit robust axonal sprouting into the cerebellum, with no apparent loss of neurons in peripheral ganglia. Given the disagreement in the literature over whether pro-NGF exerts neurotrophic or apoptotic effects, we assessed the relative levels of proNGF and mature NGF in the cerebella of these transgenic mice. Blinded western blot analyses revealed that proNGF was the major species in both transgenic and wild type mice, with very low levels of mature NGF expression. While transgenic mice displayed significantly higher levels of cerebellar proNGF protein as compared to wild type mice, both strains possessed comparable levels of mature NGF. These data reveal that the ectopic expression of NGF in the cerebellum results in an increase in proNGF rather than mature NGF levels. Together with the robust axonal growth and lack of neuronal death in the ganglia in these animals, our results are clearly consistent with proNGF exhibiting neurotrophic activity in vivo.