Trophic mechanisms regulate mitotic neuronal precursors: role of vasoactive intestinal peptide (VIP)

While trophic support from targets depends on innervation, recent evidence suggests that local VIP promotes survival of sympathetic neuroblasts prior to target interactions, during the period of neurogenesis. Developmental studies now indicate that VIP expression peaks at embryonic day 15.5 (E15.5) in sympathetic ganglia in vivo, decreasing 3-fold by birth. The expression pattern in vivo paralleled the time course of ganglion neuroblast mitosis and peptide promotion of survival in culture. In contrast, nerve growth factor (NGF) exhibited a reciprocal trophic relationship, primarily supporting older neurons that were unresponsive to VIP. To define relationships of trophism to mitosis, serial time-lapse photography was employed to document the fate of neuroblasts produced by cytokinesis in vitro. In the absence of trophic factors, up to 80% of newly born cells died by 48 h, while virtually all neuroblasts survived in response to VIP plus NGF. In addition, trophic factors elicited multiple rounds of precursor division and an increase in absolute cell number, indicating that both trophic and mitogenic mechanisms contribute to proliferation. In aggregate, these observations suggest that VIP is expressed locally during a critical fetal period, providing trophic support to dividing ganglion neuroblasts prior to the action of target-derived NGF.