Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells

Arrest of cell division is a prerequisite for cells to enter a programof terminal differentiation. Mitogenesis and cytostasis of neuronalcell precursors can be induced by the same or by different growthor trophic factors0-9. Response of PC12 cells to nerve growthfactor (NGF) involves a proliferative phase that is followed bygrowth arrest and differentiation. Here we present evidence thatthe cytostatic effect of NGF is mediated by nitric oxide (NO), asecond messenger molecule with both para- and autocrine proper-ties that can diffuse freely and act within a restricted volume . We show that NGF induces different forms of nitric oxide synthase (NOS) in neuronal cells, that nitric oxide (NO) acts as a cytostaticagent in these cells, that inhibition of NOS leads to reversal ofNGF-induced cytostasis and thereby prevents full differentiation, and that capacity of a mutant cell line to differentiate can berescued by exogenous NO. We suggest that induction of NOS isan important step in the commitment of neuronal precursors andthat IOS serves as a growth arrest gene, initiating the switch tocytostasis during differentiation.