Multiple mitogenic signalling pathways in chromaffin cells: a model for cell cycle regulation in the nervous system.

Adult rat chromaffin cells proliferate in vivo in response to neurally derived signals. Their proliferation in vitro is stimulated either by peptide growth factors or by activators of adenylate cyclase or protein kinase C that mimic the effects of neurotransmitters in adrenal medullary nerve endings. Differing susceptibilities to inhibitors and potentiators suggest that growth factors, cyclic AMP-dependent protein kinases and protein kinase C act via partially distinct and partially overlapping signalling pathways. Depolarization inhibits the mitogenic response to NGF, through a mechanism that apparently involves activation of voltage-gated calcium channels, while sparing the response to phorbol esters that activate PKC. Activators of adenylate cyclase also inhibit the response to NGF. The findings suggest that during normal development, neurally derived signals supersede growth factors in regulating proliferation of chromaffin cells by selectively inhibiting or co-opting portions of growth factor signalling pathways. This model might be generally applicable to the development of the nervous system.