Autocrine regulation of proliferation of cerebellar granule neurons by nerve growth factor

Premigratory cerebellar granule neurons, which highly express nerve growth factor (NGF), low (gp75NGFR) and high (gp140trkA) affinity NGF receptors, were used as a physiological model to investigate the effects of NGF on neuronal replication. Studies in vivo and on cultures showed that NGF stimulates DNA synthesis, mitotic activity and related cell acquisition by initiating the entry of cells into the S phase and regulating their time in the G1 and S phases. The NGF-induced effects were blocked in vivo and in vitro by both monoclonal anti-blocked in vivo and in vitro by both monoclonal anti-NGF and anti-gp75NGFR antibodies. These results clearly demonstrate that NGF is essential for the crucial first step of cerebellar ontogenesis and support the idea that low affinity receptors are involved in the biological response, possibly by interacting with gp140trkA. By comparison with a number of well known mitogens, the high affinity form could be the main transducer of the mitogenic signal pathway. The early developing cerebellum appears therefore to be the first autocrine (and/or paracrine) model of NGF action on neurogenesis in the CNS.