MULTIPLE MITOGENIC SIGNALING 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 prote in kinase C that mimic the effects of neurotransmitters in adrenal med ullary nerve endings. Differing susceptibilities to inhibitors and pot entiators suggest that growth factors, cyclic AMP-dependent protein ki nases and protein kinase C act via partially distinct and partially ov erlapping signalling pathways. Depolarization inhibits the mitogenic r esponse to NGF, through a mechanism that apparently involves activatio n of voltage-gated calcium channels, while sparing the response to pho rbol esters that activate PKC. Activators of adenylate cyclase also in hibit the response to NGE. The findings suggest that during normal dev elopment, neurally derived signals supersede growth factors in regulat ing 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.