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 program of terminal differentiation. Mitogenesis and cytostasis of neuronal c ell precursors can be induced by the same or by different growth or tr ophic factors(1-9). Response of PC12 cells to nerve growth factor (NGF ) involves a proliferative phase that is followed by growth arrest and differentiation. Here we present evidence that the cytostatic effect of NGF is mediated by nitric oxide (NO), a second messenger molecule w ith both para- and autocrine properties ties that can diffuse freely a nd act within a restricted volume(10-14). We show that NGF induces dif ferent forms of nitric oxide synthase (NOS) in neuronal cells, that ni tric oxide (NO) acts as a cytostatic agent in these cells, that inhibi tion of NOS leads to reversal of NGF-induced cytostasis and thereby pr events full differentiation, and that capacity of a mutant cell line t o differentiate can be rescued by exogenous NO, We suggest that induct ion of NOS is an important step in the commitment of neuronal precurso rs and that NOS serves as a growth arrest gene, initiating the switch to cytostasis during differentiation.